A genetically normal human has a maternal copy and a paternal copy of 23 different chromosomes. With 23 pairs of each chromosome, a genetically normal human has 46 chromosomes total. There are exceptions — for example, sperm cells are haploid and contain only one copy of each chromosome (23 chromosomes total). The number of chromosomes within a haploid cell is referred to as n. Thus, a cell with 2 copies of each chromosome (a diploid cell) has 2n chromosomes; a cell with 3 copies of each chromosome (a triploid cell) has 3n chromosomes; and a cell with 4 copies of each chromosome (a tetraploid cell) has 4n chromosomes.
Not including reproductive cells, if an individual has any other than 2n chromosomes then they are heteroploid. If a heteroploid has an exact multiple of n chromosomes (such as 69 or 92, in humans) then that individual is euploid. If a heteroploid does not have an exact multiple of n chromosomes (such as 45, 47 or any value ≠ 46) then that individual is aneuploid. Although rare, triploidy and tetraploidy are forms of euploidy. Paternal chromosome triploids (individuals with an extra copy of every paternal chromosome) have abnormal placentas and are known as partial hydatiform moles; however, maternal chromosome triploids are spontaneously aborted early during gestation.
Aneuploidy is more common than euploidy. Most aneuploidy is trisomy (three copies of an individual chromosome, instead of a pair) or monosomy (one copy of an individual chromosome). The most common trisomy is trisomy 21, which occurs in 95% of Down Syndrome patients. Chromosomes 21, 13 and 18 contain the fewest genes of any other chromosome — trisomy of any chromosome other than these three deadly. Monosomy of any chromosome except Chromosome X (a condition called Turner Syndrome) is lethal. Aneuploidy is usually caused by meiotic nondisjunction, meaning that (usually during meiosis I) chromosomes fail to disjoin properly and daughter cells either have too many or too few chromosomes.
Chromosome structure abnormalities can be either unbalanced rearrangements or balanced rearrangements. The various kinds of unbalanced rearrangements are detailed below. Unbalanced rearrangements involve deletion, duplication or both. Deletion of a chromosome segment leads to partial monosomy of that segment. Duplication of a chromosome segments leads to partial trisomy of that segment. Any mutation leading to an imbalance like monosomy, trisomy or other can result in an abnormal phenotype.
| Kind | Overview |
|---|---|
| Deletions |
A deletion is loss of a chromosome segment. There are two kinds of deletions: terminal, at the end of a chromosome; and interstitial, along a chromosome arm. Deletions can occur if a chromosome simply breaks and part of it floats away. Also, deletions can occur of misaligned chromatids cross over unequally. In addition, deletions can occur if balanced translocations or inversions segregate abnormally. A carrier individual — with one chromosome carrying the deletion, and another chromosome lacking the deletion — is monosomic for the affected genes. Monosomy usually leads to haploinsufficiency, which arises when two copies of a gene are necessary and only one copy is insufficient. Monosomy of a hormone-encoding gene is usually haploinsufficient, since one gene copy cannot encode for enough production of that hormone. |
| Duplications | Duplications, like deletions, can arise by unequal crossing over or abnormal segregation. Phenotypic abnormalities can arise if the duplication results in an extra gene copy (partial trisomy), leading to over-expression. Also, duplications within a gene can destroy its function, thus leading to haploinsufficiency. |
| Markers & Rings |
Marker chromosomes (aka supernumary chromosomes or extra structurally abnormal chromosomes) are very small and unnamed chromosomes which usually exist in addition to a normal diploid. Marker chromosomes usually consist of just centromeric heterochromatin. Larger marker chromosomes, though, contain some material from one or both chromosome arms; this disruption can lead to phenotypic abnormalities. Neocentromeres are marker chromosomes stable during mitosis which lack centromeric DNA, but which somehow have centromere activity. When a chromosome undergoes two breaks, chromosomal DNA can separate and form a ring structure. This form of marker is known as a ring chromosome. Although quite rare, ring chromosomes containing centromeric DNA are mitotically stable. However, sometime sister ring chromatids can tangle while trying to separate during anaphase. This tangling can lead to breakage, resulting in demise of the ring chromosome or even causing new ring chromosomes to form of unequal size. Thus, ring chromosomes are rarely found in all of an organism’s cells. High-resolution banding is ineffective at detecting marker chromosomes because most makers are too small to even discern the bands. However, FISH using probes for centromeric heterochromatin can usually visualize marker chromosomes. |
| Isochromosomes | Isochromosomes arise when one arm of a chromosome goes missing, and the remaining arm is duplicated to form a mirror image. In a diploid cell, this leads to partial trisomy of the genetic material from one arm (the duplicate arms, and arm on the homologous chromosome) and partial monosomy of the genetic material from the other arm. |
| Dicentrics | Although very rare, a dicentric occurs when centromere-containing fragments fuse together to form a new chromosome with two centromeres. Dicentrics can be mitotically stable if one centromere is inactivated, or if the chromosome is pseudodicentric. A pseuodicentric chromosome has centromeres which move to only one pole or the other during anaphase. |
High-resolution banding can detect deletions and duplications on the magnitude of several thousand base-pairs, and FISH can detect very small or uncertain deletions.
Chromosome structure abnormalities can be either unbalanced rearrangements or balanced rearrangements. Balanced rearrangements usually do not lead to phenotypic abnormalities; all genetic information is present in the right amount, just in a different order or in the wrong location.
| Kind | Overview |
|---|---|
| Inversions |
An inversion occurs in two steps: a chromosome breaks in two locations; the chromosome refuses with the segment between the breaks inverted. When both breaks are in the same arm, the inversion is paracentric; when there is one break in each arm, the inversion is pericentric. Paracentric inversions do not usually affect phenotype, and are hard to detect using banding or FISH. However, offspring of an inversion carrier are at risk because a loop forms when paternal and maternal chromosomes cross over; aberrant recombinations can occur within this inversion loop. Pericentric inversions, though, can lead to unbalanced gametes with duplication and deficiency of chromosome segments. |
| Translocations |
Translocation is the exchange of chromosome segments, usually between nonhomologous chromosomes. There are two primary types of translocations: reciprocal translocations and Robertsonian translocations. A reciprocal translocation occurs when segments from nonhomologous chromosomes break off, with segment attaching to the other chromosome and vice-versa. A Robertsonian translocation occurs when two acrocentric chromosomes (chromosomes with tiny short arms, meaning the centromere is near one end) fuse at the centromere and lose their short arms. Reciprocal translocations usually involve only two chromosomes, meaning the total chromosome number is unchanged. Reciprocal translocation are typically harmless, despite being more common in individuals so retarded that they require institutional care. There are three kinds of reciprocal translocation: alternate; adjacent-1; and adjacent-2. Robertsonian translocations lead to a balanced karyotype with only 45 chromosomes. Because acrocentric short arms contain just multiple copies of ribosomal RNA genes, loss of acrocentric short arms is not phenotypically important. A third type of translocation — an insertion — occurs when a segment from one chromosome inserts into a different chromosome (either in its original orientation, or inverted). Inversion translocations are rare because they require three chromosome breaks. Abnormal segretation in insertion carriers can lead to offspring with deletions or duplications of the inserted segment. Alternatively, offspring can be normal or balanced carriers. |
A mutation is any change in the nucleotide sequence or arrangement of DNA; mutations are one of only four evolutionary agents. There are three categories of mutations: genome mutations, which arise from chromosome missegregation and change how many intact chromosomes are in a cell, leading to aneuploidy; chromosome mutations, which arise from chromosome rearrangement and restructure an individual chromosome; and gene mutations, which are base pair mutations affecting an individual gene. An inherited mutation is a mutation passed on from ancestors; a de novo mutation is a new and non-inherited mutation. Disease mutations interfere with protein synthesis at one of the steps in the list to the bottom right.
Somatic mutations are not passed on to progeny and only affect some cells of the body; a tumor is a common example of a somatic mutation. Germline mutation affect germ cells (cells which differentiate into eggs or sperm) and are passed onto progeny. Many germline mutations occur either in the fertilized egg (the zygote), leading to both germ and somatic cells containing the mutation. Dynamic mutations worsen during gametogenesis, leading to a worsened phenotype in each generation. Examples of dynamic mutations include Huntington Disease and Fragile X Syndrome, which involve repeat sequences extending during gametogenesis.
Some mutations are more likely to be maternal and other mutations are more likely to be paternal. Primary oocytes develop fetally and ovulate years and decades later; the older an oocyte is, the more likely it is to undergo nondisjunction. This nondisjunction leads to trisomy (which can be viable) and monosomy (which is almost never viable). For this reason, aneuploidy is maternal in at least 80% of all cases and occurs more often with maternal age. On the other hand, spermatogenesis occurs throughout a man’s entire life. With mutations accumulating during each round of replication, point mutations are almost always paternal and increase with paternal age.
Point mutations are substitutions of one base pair for another. A transition is when one pyrimidine is swapped for another — such as C for T, or T for C — or one purine is swapped for another — such as A for G, or G for A. A transversion is when a pyrimidine and a purine swap. Transitions are more frequent because when cytosines methylate to form 5-methylcytosine, they can spontaneously deaminate to thymidine.
| Missense Mutation | A missense mutation is the changing of a single base-pair. Within a coding region, this usually leads to a change of a single amino acid in the protein product. However, if this mutation is in the 5′ or 3′ untranslated region then a missense can lead to underexpression of the protein product. |
|---|---|
| Nonsense Mutation | A nonsense mutation (aka chain termination mutation) is the replacement of a codon encoding an amino acid with a stop codon. This stop codon ends transcription of that gene prematurely, with an incomplete and unstable mRNA formed. Most of these mRNAs just fall apart; however, the few that are translated result in truncated proteins that quickly disintegrate. |
| RNA Processing Mutation | An RNA processing mutation interferes with splicing of mRNA. If the point mutation alters a splice donor or splice acceptor site, then RNA splicing is interfered with or abolished at that location. If the point mutation creates a new splice donor or splice acceptor site, then this new site competes with normal splicing and the processed mRNA might still contain introns. |
There are deletions (removal of DNA), insertions (addition of DNA), inversions (reversal of the orientation of a DNA segment), translocations (moving of a DNA segment) and combinations thereof. Some deletions and insertions are small changes which are detectable only via PCR or genome sequencing; these usually shift the reading frame (a frameshift mutation) and lead to truncation of the mRNA by an early stop codon in the new reading frame. Some larger mutations can be detected via Southern blotting. For a mutation to be detectable by chromosome banding, it must involve at least 2 million base pairs.
Deletions, insertions, inversions and translocations often arise via faulty recombination. For example, unequal crossing over is crossing over without proper exchange of genetic information, leading to insertions in one chromosomes and deletions in another. Another form of faulty recombination is when mispaired chromosomes or sister chromatids exchange genetic information.
| Mutation | Example | Overview |
| Missense | Phe15Tyr | A missense mutation is described by the wild-type amino acid, its residue and the resulting mutant amino acid. The example shows a mutation where a phenylalanine is converted to tyrosene at residue 15 of a gene. |
|---|---|---|
| Nonsense | Ser25X | A nonsense mutation is described by the wild-type amino acid, its residue and then an X to represent the mutant stop codon. The example shows a mutation where serine is replaced with a stop codon at residue 25 of a gene. |
| Nucleotide Change | g.3000G>A c.1000g>a |
If the full genomic sequence is known, a nucleotide change is denoted by a prefix (g for genomic and c for cDNA), followed by the number of that nucleotide, the original nucleotide, a ‘>’ symbol, and finally the mutant nucleotide. Mutations identified in genomic DNA are denoted with capitalized nucleotides; mutations identified in non-genomic DNA are denoted with lower-case nucleotides. The first example shows a genomic mutation at position 3,000 where a G transitions to an A; and the second example shows the same mutation at position 1,000 on cDNA. |
| g.IVS25+2G>A g.IVS25-2T>A g.IVS25-2A>T |
If the full genomic sequence is not known, then nucleotides are counted either: up from the 5′ splice donor site, with +1 being the invariant G of the GT at the 5′ splice donor site; or down from the 3′ splice acceptor site, with -1 being the invariant G of the AG at the 3′ splice acceptor site. The first example shows a transversion at the T of the 5′ splice donor site; the second example shows a transversion at the A of the 3′ splice acceptor site. | |
| Deletions | c.1000_10003delGCAT | Small deletions begin with a prefix (g or c for genomic or cDNA), followed by the locations of the deleted nucleotides, then a del for deletion, and finally the nucleotides deleted. The example shows a four-nucleotide deletion of a G,C, A and T at respective locations 1000, 1001, 1002 and 1003. |
| Insertions | c.1000_10001insATGC | Small insertions begin with a prefix (g or c for genomic or cDNA), followed by the nucleotides flanking the insertion, then an ins for insertion, and finally the nucleotides inserted. The example shows an insertion of A,T,G and C between nucleotides 1000 and 1001. |
| Nomenclature table derived from Nussbaum, McInnes & Willard: Genetics in Medicine, 7th ed. Philadelphia, Saunders, 2007. (pg 181) | ||
| Effect | Example | Overview |
| Loss of Function | α-thalassemia β-thalassemia Turner Syndrome Retinoblastoma |
Loss of function mutations leads to a lower gene dosage. Examples of loss of function diseases are the α-thalassemias (where the entire α-globin gene is deleted), β-thalassemias (premature stop codon or coding missense), Turner Syndrome (a monosomy where a chromosome is lost) and retinoblastoma (where a somatic mutation lead to loss of function of tumor-suppressor genes). Many loss-of-functional diseases are less severe in heterozygotes; oftentimes, a single functional allele is enough for a healthy or mild-diseases phenotype. |
|---|---|---|
| Gain of Function | Trisomy 21 Charcot-Marie-Tooth 1A Hemoglobin Kempsey Achondroplasia |
Gain of function mutations lead to increased activity of a certain protein in tissues which normally express it (as opposed to heterocrhonic or ectopic expression). This increased activity can be due to a higher gene dosage, as in Down Syndrome (a third copy of part or all of Chromosome 21) or Charcot-Marie Tooth Type 1A (duplication of a particular gene) or even progression of certain cancers. Alternatively, one function of a protein might be detrimentally hyperactive. Examples include: hemoglobin Kempsey, a mutant hemoglobin with such high oxygen affinity that it does not release oxygen to tissues; and achondroplasia, where an over-strong signal (from exceptional binding of a growth factor receptor) leads to growth retardation. |
| Novel Property | Sickle Cell | Novel property mutations give encoded proteins new properties. For example, the hemoglobin chains of sickle cells aggregate into long fibers which deform the cell and impair its function. Some novel property mutations are also loss of function mutations; mutants with novel glycosylation sites are rendered inactive by glycosylation. |
| Heterochronic & Ectopic Expression |
Some Cancers | Certain mutations are simply due to gene expression at the wrong time (heterochronic) or in the wrong tissue (ectopic). For example, constitutive expression of proliferation genes (known as oncogenes) can lead to tumor formation. |
There are numerous diseases which arise from expansions in (CAG)n repeats, which encode glutamine. In a coding region, a (CAG)n repeat expansion can either inactivate a protein or exhibit a dominant phenotype due to poly-glutamine’s toxic effects; examples include Huntington Disease and Spinocerebellar Ataxia (SCA) type I. In a non-coding region, a (CAG)n repeat expansion can interfere with chromatin structure and disrupt transcriptional regulation, and/or exhibit a dominant phenotype by distracting splicing factors with the triplet repeat; examples include Myotonic Dystrophy, Fragile X Syndrome and other SCA forms.
Patients with Chronic Myelogenous Leukemia have undergone a translocation between chromosomes 9 and 22 to form a Philadelphia chromosome (so named due to where it was discovered) containing the tip of chromosome 9 and a portion of chromosome 22, and with an activated oncogene.
Thalassemias are a heterogeneous group of hemoglobinopathies whereby a reduction in synthesis/stability of α or β globin chain causes α- or β-thalassemia, respectively. The clinical problem is excess β peptides (in α-thalassemia) or excess α peptides (in β-thalassemia); this imbalanced α:β ratio leads to early cell destruction and iron overload. The chain produced at a normal rate becomes relatively overabundant, eventually precipitating in the cell, damaging the membrane and causing premature hemolysis.
The heterozygote advantage is that thalassemias weaken red blood cells and confer some resistance to malaria. Upon infection, the cell just dies and prevents spread. Individuals that are α-α-/α-α- die in utero, although this does not include heterozygous mutations in different globin genes. Expression of the globin gene locus is managed by a locus control region (LCR).
| Treatment | Overview |
|---|---|
| Drug Therapy | Possible drug therapy to influence LCR to prolong γ-globin (fetal) expression. |
| Gene Therapy | Using a lentivirus vector to add back normal β-globin gene or normal γ-globin (fetal) genes. Attempts without a new LCR failed; additions require the LCR for consistent, strong globin expressionAdditions require LCR in the construct for consistent, strong globin expression. Early attempts failed without the LCR. |
β-globin deficiency. Mostly due to single base-pair substitutions in the β-globin genes. Much more heterogenous than α thalassemias, even in high frequency populations. Complex β thalassemias involve β globin plus one or more of the genes from the β globin cluster LCR. β globin cluster is totally dependent on its LCR for expression.
Due to α-globin deficiency. Excess γ-globin chain form g4 tetramer (Hb Bart’s). Excess β-globin chains form b4 tetramer ( Hb H). These are ineffective oxygen carriers.
Nearly all disease genes have mutant alleles which affect splicing of the mRNA, rather than protein coding. Exon skipping can arise via mutations in the 5′ splice site, the 3′ splice site, and/or exonic or intronic splicing enhancers. Activation of cryptic splice sites (thus shortening the exon) can arise via mutated exonic splicing enhancers. Examples of diseases due to mRNA splicing errors include Familial Isolated Growth Hormone Deficiency (mutations in the GH-1 gene), Cystic Fibrosis (mutations in the CFTR gene), Spinal Muscular Atrophy and some thalassemias (mutations in the β-globin gene that activate a cryptic 3′ splice site).
Spinal Muscular Atrophy is the most common genetic cause of infant death, occurring in 1 in 6,000-10,000 births. This is an autosomal recessive disorder caused by mutations in the SMN1 gene, encoding a protein involved in snRNP maturation. Humans have undergone an SMN gene duplication generating the SMN2 gene. Even though it encodes an identical protein, the presence of SMN2 cannot compensate for the loss of SMN1 in spinal muscular atrophy, because its splicing is abnormal and it does not produce functional protein.
Splicing targeted therapies are being tested for Spinal Muscular Atrophy. A single C to T mutation in an exonic splicing enhancer of SMN2 exon 7 causes exon skipping and production of a truncated protein from 80% of the SMN2 mRNA. If drugs or other therapies could be found that increase exon 7 splicing of SMN2, one could potentially treat the disease even without correcting the SMN1 defect.
A hemoglobinopathy is any disorder of hemoglobin, the red blood cell protein which binds oxygen. Oxyhemoglobin has a reduced orion (does not carry oxygen); methemoglobin has an oxidized iron (carries oxygen). Methemoglobin reductase reverses the oxidation, thus unload the oxygen. Some mutant hemoglobin is resistant to methemoglobin reductase, and the heme iron thus remains permanently oxidized. Heterozygotes accumulate methemoglobin, leading to asymptomatic cyanosis (blue skin). Homozygotes are completely unable to unload oxygen and have thus not been found. Separate from reductase-resistant methemoglobin are diseases where hemoglobin has altered oxygen affinity. For example, Hb Kempsey binds oxygen very strongly and cannot unload oxygen to tissues. Encoded by an autosomal dominant, Hb Kempsey heterozygotes over-proliferate RBCs in an attempt to resolve low oxygen levels in tissues; HB Kempsey is lethal for homozygotes.
Clinically significant structural variants of normal hemoglobin are synthesized in the proper amount, but have structural defects which can cause or interfere any of the mechanisms described below. Structural variants are typically caused by point mutations, and are responsible for Sickle Cell Disease. Recall that Amino1#Amino2 means ‘Amino1′ replaced ‘Amino2′ at position ‘#’ on the polypeptide.
| Hb | Impact | Usual Mutation | Overview |
| HbS | Hemolytic Anemia | β Chain: Glu6Val | HbS is responsible for the automosal recessive Sickle Disease Disease. |
|---|---|---|---|
| HbC | Hemolytic Anemia | β Chain: Glu6Lys | Oxygenated HbC crystalizes, causing mild hemolysis and circulatory obstruction. |
| HbH | Hemolytic Anemia | β Chain: Phe42Ser | Hb Hammersmith (β4) is unstable, precipatory, hemolytic and autosomal dominant. |
| HbM | Oxygen Transport | β Chain: His92Tyr | Methemoglobin cannot unbind oxygen, causing cyanosis. Autosomal dominant. |
| HbK | Oxygen Transport | β Chain: Asp99Asn | Hb Kempsey cannot unbind oxygen, causing autosomal dominant polycythemia. |
| HbE | Thalassemia | β Chain: Glu26Lys | Autosomal recessive thalassemia due to mutant structure and reduced synthesis. |
| Clinical Significance | Overview |
| Hemolytic Anemia | Hemolytic anemia (lysis of red blood cells) is typically caused by an unstable hemoglobin. Notable exceptions are HbS (sickle cell hemoglobin) and HbC, which are very stable but still detrimental to RBCs. |
|---|---|
| Oxygen Transport | Altered oxygen trasnport is caused by mutant hemoglobin with increased or decrease oxygen affinity. An example is methemoglobin, which is incapable of releasing bound oxygen (as opposed to oxyhemoglobin, which can reversibly oxygenate). |
| Thalassemia | When one hemoglobin chain is unavailable, abnormal hemoglobin form which do not function properly. This condition — thalassemia — causes anemia. Also, hemolysis results from extremely unstable abnormal hemoglobin which may form. |
A hydatid cyst (also known as a mole) is a mass of placenta-derived cells resembling a grape cluster. Complete hydatidiform moles contain only paternal chromosomes but have a 46,XX karyotype. Complete hydatidiform moles (or complete moles, for short) develop into a hydatid cyst. Complete moles contain no normal placenta and no fetus. Ovarian tetranomas are cases with only maternal chromosomes which exist only as benign tumors.
Partial hydatidiform moles (or partial moles, for short) are triploids containing either an extra maternal chromosome set or an extra paternal chromosome set. Cases with an extra set of maternal chromosomes are severely retarded with small, fribrotic placentas. Cases with an extra set of paternal chromosomes have abundant trophoblast (“pre-placental”) growth and poor embryonic development.
X-Linked Severe Combined Immunodeficiency (SCID) stems from a mutation in either common γ chain gene or IL-7 receptor-α gene. A mutation in the common γ chain gene leads to an inability to bind (and hence respond) to cytokines IL-2,4,7,9,15,21. Without activity of those cytokines, the individual cannot produce T cells, B cells nor NK cells; the patient has bubble boy disease and almost no ability to fend off infection. A mutation in the IL-7 receptor-α gene leads to a lack of T cells but present B cells and NK cells. Based on this — and the paragraph above — it is clear that IL-7 is critical for T cell formation, but not B cell nor NK cell formation.
It is worth noting that mice require IL-7 for both T cell and B cell formation. SCID mice are extremely useful research tools. Lacking B and T cells, they are unable to mount an adaptive immune response. Thus, they do not reject transplanted tissues and are also useful for studying how to restore hematopoiesis. Also, SCID has been successfully treated via gene therapy techniques to introduce a functioning common γ chain gene into hematopoietic stem cells.
Down Syndrome (aka trisomy 21) is one of only three thoroughly-studied viable non-mosaic autosomal disorders (the others being trisomies 13 and 18), all of which result in stunted growth, mental retardation and multiple congenital deformities. The phenotype of Down Syndrome involves: hypotonia (low muscle tone) at birth; dysmorphic facial features; folded, low-set ears; flat nasal bridge; mental retardation, with an average adult IQ or 30-60; and, in about a third of all cases, congenital heart disease.
Down Syndrome is the most frequent and studied chromosomal disorder, and can arise in several different ways. All of these avenues somehow involve trisomy of Chromosome 21, and are detailed below.
| Genotype | Overview |
| Trisomy 21 | Approximately 95% of Down Syndrome cases arise from meiotic nondisjunction of the chromosome 21 pair, leading to trisomy 21. This nondisjunction is maternal in 90% of cases, usually occurring during meiosis I. In the paternal 10% of cases, the nondisjunction usually occurs in meiosis II. |
| Robertsonian Translocation | Approximately 4% of Down Syndrome patients have Robertsonian translocations. These patients arise when the long arm of Chromosome 21 (Chromosome 21q) fuses with the long arm of another chromosome, and the short arms break off (but are not considered their own chromosome). If this occurs during meiosis, then cells arise that are trisomic for Chromosome 21q, with: 2 normal Chromosome 21′s; and a Robertsonian chromosome containing Chromsome 21q and the long arm of another chromosome. Usually a translocation with Chromosome 14, this Robertsonian chromosome is denoted der(14;21). |
| 21q21q Translocation | Actually an isochromosome, this situation usually occurs postzygotically when one Chromosome 21 breaks apart into a short arm and a long arm; the long arm duplicates, forming a chromosome composed of two Chromosome 21 long arm. |
| Mosaic Down Syndrome | Accounting for approximately 2% of patients, mosaic Down Syndrome can range from very mild to very severe, depending on the number of affected cells. This variability possibly reflects what proportion of embryonic cells carried the disease genotype. |
| Partial Trisomy 21 | There are a few rare patients who have trisomy of only a portion of Chromosome 21; these patients give tremendous insight into which genes are responsible for disease when triplicate. |
Trisomy 18 is one of only three thoroughly-studied viable non-mosaic autosomal disorders (the others being trisomies 18 and 21), all of which result in stunted growth, mental retardation and multiple congenital deformities. Trisomy 18 frequently arises via translocation of all or most of Chromosome 18. Trisomy 18′s phenotype is mental retardation in all cases, with most cases also involving: severe heart malformation; a receded jaw (overbite); low-set malformed ears; rocker-like feet; and hypertonia, usually leading to unique clenched fists characteristic of trisomy 18.
Trisomy 13 — occurring in 1 in ∼20,000 births — is one of only three thoroughly-studied viable non-mosaic autosomal disorders (the others being trisomies 18 and 21), all of which result in stunted growth, mental retardation and multiple congenital deformities. Trisomy 13 (aka Patau Syndrome) leads to severe growth and mental retardation, usually accompanied by: a sloped forehead; malformed ears; clenched fists and rocker-bottom feet (as in trisomy 18); congenital heart defects; urogenital defects; and polycystic kidneys. Most trisomy 13 individuals gain their extra chromosome via maternal nondisjunction in meiosis I.
Many thanks to ThereseAnn, the commenter who provided incredible links to learn more about trisomy 13. I urge StudentReader.com visitors to peruse LivingWithTrisomy13.org, a site about fellow human beings living with Trisomy 13.
Sickle cell hemoglobin (HbS) results from a single nucleotide substitution which changes the codon of the sixth β-globin amino acid from glutamic acid to valine (GAG→GTG: Glu6Val) and is the causative agent of sickle cell disease when homozygous. Homozygotes have α2Aβ2S hemoglobin. Heterozygotes (said to have sickle cell trait) have α2Aβ2S (HbS), α2Aβ2A (HbA) and α2Aβ2Sβ2A (HbS/HbA hybrid) hemoglobin, and are clinically normal despite mild symptoms under low oxygen pressure. In Sickle Cell Disease, the HbS β chains form chains, aggregating into long fibers which deform the cell, impair its function and result in hemolysis for homozygotes.
Hyperphenylalaninemias are enzymopathies (enzyme inactivity) and aminoacidopathies (inappropriate amino acid processing) that lead to an increase in phenylalanine blood levels due to improper pheylalanine catabolism. They are all autosomal recessive and exemplified by phenylketonuria and phenylalanine hydroxylase deficiency. All hyperphenylalaninemias stem from loss of function in phenylalanine hydroxylase (PAH or PheH, a liver enzyme which catabolizes phenylalanine to tryosine) and/or genes required to synthesize its cofactor, tetrahydrobiopterin (BH4).
Classic phenylketonuria (PKU) stems from an autosomal recessive PAH mutation that renders it inactive. Unable to degrade phenylalanine, PKU patients accumulate phenylalanine in their body fluids and the ensuing hyperphenylalaninemia damages the developing nervous system and mature brain. It is treated by complete diet restriction of phenylalanine; if no phenylalanine is ingested, then it cannot accumulate in the body. Phenylalanine hydroxylase variants are frequently benign, with many people being heterozygous at the gene encoding PAH. The few clinically significant PAH alleles can lead to near-complete PAH activity (classic PKU) or variant PKU (aka non-PKU hyperphenylalaninemia). Variant PKU occurs when PAH carries enough residual activity to lessen the disease phenotype, or prevent the disease despite elevated phenylalanine blood levels.
Rarely, a patient with hyperphenylalaninemia will have normal PAH but be unable to properly synthesize or recycle its cofactor, tetrahydrobiopterin (BH4). Since BH4 is necessary for the activity of other enzymes, phenylalanine restriction alone will not fully treat the patient. Fortunately, normal BH4 can be administered in large oral doses that allow normal development and even unrestricted consumption of phenylalanine. In addition, BH4 administration can help lower phenylalanine blood levels in patients whose PAH has a weak BH4 affinity.
Hyperphenylalaninemias lead to mental retardation due to an imbalance of amino acids crossing the blood brain barrier. With too much phenylalanine in the bloodstream, other amino acids are outcompeted and their levels in the brain significantly decrease. This decrease in brain levels of other amino acids leads to disruption of brain development and, to a lesser extent, mature brain function. Patients with PKU are allowed slight flexibility in their diet during adulthood, as elevated phenylalanine blood levels will not have as detrimental an effect after development. However, elevated phenylalanine levels are detrimental for fetal life. Thus, females with hyperphenylalaninemia expecting to conceive must vigorously restrict their phenylalanine consumption to avoid severe developmental retardation in their offspring.
Lysosomes are membrane-bound organelles which contain hydrolases that degrade unneeded proteins and infectious bacteria. When these substrates accumulate without degradation inside the lysosome, the cells die lysosomal storage diseases (a subset of enzymopathies ensue. Affected tissues grow noticeably large, and mental dysfunction occurs in diseased brains. Tay-Sachs disease is a group of disorders where hexosaminidase A (hexA) cannot degrade the sphingolipid GM2 ganglioside. Since GM2 ganglioside synthesis is most prevalent in the brain, it is most severely affected by Tay-Sachs.
Normal hexA consists of α and β subunits (encoded by HEXA and HEXB) that associates with an activator protein to cleave GM2 ganglioside. Disruption of the α subunit leads to Tay-Sachs disease; disruption of the β subunit o the activator protein leads to, respectively, Sandhoff disease and activator protein deficiency. Tay-Sachs homozygotes are clinically normal at first, but mentally deteriorate by 3-6 months of age and die by 2-4 years. HEXA alleles with some residual activity can lead to late onset, motor dysfunction, psychosis or sometimes no disease at all.
Lysosomes are membrane-bound organelles which contain hydrolases that degrade unneeded proteins and infectious bacteria. When these substrates accumulate without degradation inside the lysosome, the cells die lysosomal storage diseases (a subset of enzymopathies ensue. Hurler Syndrome is a mucopolysaccharidose, a kind of disease involving accumulation of mucopolysaccharides (or glcyosaminoglycans) within lysosomes due to deficiencies in degradative enzymes. An autosomal recessive disease, Hurler Syndrome is caused by extreme impairment of the enzyme α-L-iduronidase, leading to facial dysmorphia, developmental retardation and death by ∼10 years. In Scheie Syndrome, also autosomal recessive, α-L-iduronidase has residual activity and patients sometimes have normal life spans and normal intelligence (despite facial dysmorphia).
Hunter Syndrome is a phenotypically similar mycopolysaccharidose, but is X-linked recessive and impairs iduronate sulfatase (not α-L-iduronidase). Hurler Syndrome fibroblasts synthesize normal iduronate sulfatase, and Hunter Sydrome fibroblasts synthesize normal α-L-iduronidase. When grown together in culture, they uptake secreted proteins and thereby complement each other to produce non-diseased cells. Complementation analysis is the study of genetic complementation, where mutant gene products can complement each other to neutralize disease.
Duchenne Muscular Dystrophy (DMD) is untreatable, severe, deteriorative and relatively common X-linked recessive disorder caused by a mutation of the structural protein dystrophin. DMD causes worsening muscle weakness, with wheelchair confinement by ∼12 years and death by ∼20 years. Females very rarely have DMD, since it is lethal in males and thus cannot be passed on to XX progeny; however, females with Turner Syndrome or X chromosome translocations have been known to have DMD. About 1/3 of DMD patients have new mutations, while 2/3 have maternal inheritance of the DMD allele.
At ∼2,300 kilobases (1.5% of the X chromosome), the gene encoding dystrophin is among the largest in the animal kingdom. It contains 79 exons, and its 7 tissue-specific promoters allow differential splicing into tissue-specific and developmentally regulated isoforms. Dystrophin is a massive complex with a myriad of functions that maintain muscle integrity. Most DMD patients have deletions in either the 5′ or central regions, while most other patients have randomly distributed point mutations. Due to its sheer size, the gene for dystrophin has one of the highest frequencies of mutation.
PCR analysis of carriers and fetuses can identify deletions in dystrophin, and molecular sequencing can identify point mutations. Also, linked markers are useful for prenatal diagnosis when direct analysis does not detect a mutation. If a DMD patient is the first affected family member and a mutant dystrophin allele is not found in his mother, then most of the time it is due to a new mutation. However, ∼10% of such cases are in fact due to maternal germline mosaicism, meaning only some of her cells carry the mutant allele; this is significant due to an increased risk of recurrence.
Cystic Fibrosis (CF) is caused by an autosomal recessive mutation of the cystic fibrosis transmembrane regulator gene (CFTR), which was identified via positional cloning. Cystic fibrosis is due to abnormal fluid and electrolyte transport across epithelial apical (pointed) membranes. This leads to disease of the lung, pancrea, intestine, hepatobiliary tree and male genital tract. Noticeable when kissing a baby with cystic fibrosis, loss of CFTR activity leads to chloride and sodium build-up in sweat glands. Also, the mucous layer of the lung becomes ‘sticky’ and traps pathogens, leading to chronic pulmonary infections..
The first sign of cystic fibrosis is usually high concentration of sodium and chloride in sweat. The average patient survives to ∼33 years, eventually succumbing to chronic lung and heart infections, and maldigestion due to a deficiency of pancreatic enzymes. Many males are infertile due to absence of a vas deferens; most females have near-normal fertility. Postnatal lower intestinal tract obstruction also may occur, treatable by surgery. Some individuals with mutations in the CFTR may have just one or all of these phenotypes.
Present on Chromosome 7 (7q31, to be precise), the CFTR gene is ∼190kB and encodes the large 170kD cystic fibrosis transmembrane conductance regulator (CFTR) protein. Likely an ABC transporter, it contains a chloride channel with five domains: two membrane-spanning domains, each of which contain six transmembrane sequences; two nucleotide-binding domains which bind and hydrolyze ATP to power opening and closing the channel; and a regulatory domain, mediated via phosphorylation.
Approximately 2% of white (European) populations carry a cystic fibrosis disease allele, although carriers are almost nonexistent in other populations. The most frequent CFTR defect is δF508, a missense mutation that reduces ATP binding and accounts for 70% of all CF alleles in white populations. Patients homozygous for δF508, or with premature stop codons in CFTR all have insufficient pancreatic activity, but differing pulmonary (lung) disease. Two alleles of a modifier gene encoding transforming growth factor β1 (TGFβ1) are frequent in cystic fibrosis patients with severe pulmonary disease. Also, a cystic fibrosis genocopy (aka phenocopy — an identical phenotype for different genetic reasons) is a mutation in SCNN1, which encodes an epithelial sodium channel. With ∼85% of CFTR disease alleles identified, DNA diagnosis is useful prenatally and to identify carriers amongst relatives of a patient with no familial history of cystic fibrosis. However, the only current treatments for cystic fibrosis are antibiotics, exercise and a nutritious diet.
Fragile X Syndrome is an X-linked mutation in FMR1, which encodes an abundant neuron protein named FMRP. Almost every FMR1 mutation is an expansion of the CGG-repeat sequence in the 5′ untranslated region of the gene. Normal individuals between 6 and 50 CGG repeats, while diseased patients have over 200 repeats. So many repeats does not happen within one generation; it takes several expansions (premutations) over several generations to acquire hundreds of CGG repeats (full mutation). Having over 200 CGG repeats leads to hypermethylation of the repeat region and the adjacent FMR1 promoter, leading to obliteration of FMRP expression. Mental retardation ensues, with a more severe phenotype in males than females. AGG triplets nestled between CGG repeats inhibit AGG expansion; thus, individuals with reduced AGG triplets are predisposed to become carriers of a diseased FMR1 allele.
Almost all males and ∼50% of females with a disease allele will have the Fragile X phenotype. Some patients have a mixture of premutant and full mutant cells (repeat length mosaicism) due to a worsening genotype with every round of mitosis. Patients with over 200 CGG repeats but lacking methylation in some of their cells (repeat methylation mosaicism) or none of their cells range from normal to fully affected. When analyzing a pedigree, increasing prevalence of the disease in successive generations and inheritance from unaffected mothers are both signs of fragile X syndrome.
Huntington Disease (HD) is an autosomal dominant, late-onset, progressively neurodegenerative disorder caused by mutation of the ubiquitously expressed HD gene. Normal HD alleles have 10 to 26 CAG repeats, while disease HD alleles typically contain more than 36 CAG repeats; 97% of disease alleles are inherited, while 3% of disease alleles are new mutations arising from inherited premutations of 20 to 35 repeats. The function of huntingtin — the gene product of HD — is unclear, and it is also unknown how huntingtin encoded by a disease allele leads to the Huntington Disease phenotype.
Age of onset is inversely proportional to the number of CAG repeats in the HD allele. Juvenile onset ensues from over 60 CAG repeats, adult onset ensues from 40-55 CAG repeats and reduced penetrance (possibly no disease phenotype) ensues from 36-41 CAG repeats. Alleles with more than 36 repeats expand during paternal transmission, with somewhat less expansion during maternal transmission. The phenotype includes cognitive loss, behavioral instability and even schizophrenia. As death approaches, motor skills fail such that incontinence and mutism develops; however, behavioral disturbances lessen. The only current treatment for Huntington Disease is pharmacologic treatment of behavioral instability, and lots of support.
Patients with two defective retinoblastoma (Rb) alleles invariably develop retinoblatomas, leading to its discovery as a tumor suppressor. E2F is a key host cell transcription factor in activating cellular genes required for synthesis of dNTPs, DNA polymerases, and other proteins required for cells to begin S-phase. Also, E2F binds and activates transcription from the adenovirus E2 promoter. The E2 region encodes viral proteins required for adenovirus DNA replication. In uninfected cells, retinoblastoma (aka Rb) is bound to E2F and inactivates it; in infected cells, Rb is not bound to E2F — the adenovirus protein E1A binds to retinoblastoma and removes it from E2F. Since E1A deactivates retinoblastoma by binding it and displacing it from E2F, it accomplishes the equivalent of mutations in both retinoblastoma alleles: there is no functional cellular retinoblastoma. SV40 and polyomavirus Large T-antigen also binds Rb; mutations of SV40 and polyomavirus Large-T that did not bind retinoblastoma did not transform cells. p110 is another tumor suppressor that was found to be absolutely identical to retinoblastoma.
| Next Steps | Study the other tumor suppressor p53 |
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