Chapter 5: Genetic Disorders
Human genetic disorders are estimates to be much more frequent than observed empirically. Such disorders can be categorized in to three types:
Single gene mutations—Generally rare in the population unless maintained by strong selective forces (as in the case with sickle cell anima). These genes follow typical mendelian patters and are usually highly penetrant.
Chromosomal disorders—Uncommon and associates with structural or numerical alteration in the autosomes or sex chromosomes.
Complex multigenic disorders—Much more common than the aforementioned. Several variant genes contribute to the change in relative risk associated with having a given disease. Each variant is likely to have low penetrance. Such diseases are alterosclerosis, diabetes mellitus, autoimmue diseases, etc.
The following types of mutations (permanent changes to the DNA) are what affect single genes. These mutations can affect transcription by affecting promoters or enhancers; processing of mRNA by affecting slice junctions or introns; or translation by affecting changing the coding sequence.
Point mutations with coding sequences—These mutations are substitutions of a single nucleotide in protein coding gene. When the change occurs in a different amino acid (e.g. valine for gultamine as in the case of sickle cell anemia) is termed a conservative missense mutation but termed a nonconservative missense mutation when the change codes for the same amino acid. Nonsense mutations refer to changes that produce a stop codon (UAA, UAG, or UGA) as can be seen in β0-thalassemia where the shortened β-globin peptide is rapidly degraded.
Mutations in noncoding sequences—Point mutations or deletions in promoters or enhancers (in noncoding regions) can lead to reduced levels or transcription of genes. Such mutations in introns can lead to defective splicing resulting in failed production of a mature mRNA sequence. Such mutations are not likely to affect transcription if they do not occur in promoters or enhancers.
Deletions and insertions—Deletions and insertions in protein coding regions can have a number of effects. Indels in multiples of 3 may lead to abnormal protein production while indels of different multiplicities typically result in a variable number of incorrect peptides before premature termination.
Trinucleotide-repeat mutation—These mutations are characterized by the dynamic expansion of tandem repeats of three nucleotides usually containing (cytosine and guanine) exemplified by the 200-4000 repeats of CGG in the familial mental retardation 1 (FMR1) gene which gives rise to Fragile X syndrome while the general population averages 29 repeats.
Most mutations lead to dysfunctional or inactive gene products. Hence, if the characterization of a dominant or recessive trait inherently depend on the whether one copy of gene can compensate for the mutated copy. Single-gene disorders typically follow three types of inheritance:
Autosomal dominate disorders are expressed in heterozygous individuals, which implies that at least one parent of an affected individual is usually affected. Females and males are affected in roughly equal proportions and can both transmit the condition. Disorders can generally be described to have the following features:
Some proportion of patients have unaffected parents—This effectively describes the rate of new mutations. Siblings will not be affected and do not have an increased risk for disease development nor are likely to have affected children.
Clinical presentation may be modified by variation in penetrance and expressivity—The penetrance of a disease is defined by the percentage of the population that contain the pathological variant allele but do not have the phenotype. Variation in expressivity is described by variations in the phenotypes of affected individuals (e.g. individuals with neurofibromatosis 1 can of some brownish spots on the skin to tumors and skeletal deformities)
Age onset varies—Symptoms may be present at birth but in may diseases signs might not appear until adulthood
Autosomal dominant disorders arising for deleterious variants can be described as one of the following:
Regulation of metabolic pathways involving feedback inhibition—As an illustrative example, the loss of 50% of the LDL rectors results in familial hypercholesterolemia
Key structural proteins—Though not fully understood why reduction in half of such protein leads to pathogenic effects, it can be easily how a mutation in a gene that codes for a subunit of a multimeric protein can interfere with the whole complex (e.g. collagen trimers hemoglobin dimers or dimers). Such mutant alleles are termed dominant negative.
Autosomal recessive disorders make up the majority of medelian disorders. Affected individuals do not usually have an effected parent, the recurrence risk for unaffected parents is 25%, the likelihood of having affected progeny, among consanguineous parents, increases dramatically (hyperbolically) as the variant becomes less frequent in the population. Autosomal recessive disorders are generally distinct from dominant disorders as follows:
Expression tends to be uniform
Complete penetrance is common
Onset is early in life
New mutations are rarely detected since the new heterozygotes are not symptomatic and progeny is not likely to mate with other carriers
Having half as many wildtype enzymes does not cause cells to have abnormal function
Almost all inborn errors of metabolism are autosomal recessive disorders.
All sex-linked disorders as X-linked and usually recessive. Mutations in the Y chromosome usually result in infertility and thus are not transmitted to progeny. There are however, homologous regions of the X and Y chromosomes termed pseudoautosomal regions, that may have pathological consequences. X-linked disorders typically have the following criteria:
Affected males do not transmit the disorder to male progeny but all female progeny are carriers for the disorder. Male progeny of heterozygous females have a 50% chance of having pathogenic variant.
A variable number of cells in carrier female may express the pathogenic variant do to X-chromosome inactivation. Such females typically have less expressivity than affected males however females be more susceptible to aggravating environmental factors (than the unaffected population) as in the case with glucose-6-phosphate dehydrogenase (G6PD) deficiency, which cases red cell hemolysis.
There are some X-linked dominant disorders that are much less common. Such disorders usually result in failure to bring XY fetuses to term. An affected mother will have affected progeny half the time (both among XX and XY) and the progeny of an affected father will be affected progeny 100% (among XX) and 0% (among XY) of the time. Vitamin-D resistance rickets is an example of such a disorder.
Mendelian single-gene disorders lead to malformation of a protein or reduction of a gene product. The inheritance, penetrance, and expressivity can be explained in part but the kinds of proteins affected. This texts describes 4 mechanisms of single-gene disorders: (1) enzyme defects and consequences; (2) defective membrane receptors and transport proteins; (3) alteration in structure, function and quantity of non-enzyme proteins; (4) gene variants resulting in unusual reactions to drugs.
Pathogenic variant often result in enzymes with reduced functionality or reduce amounts of enzymes the consequence of either case is a metabolic block leading three major consequences.
Accumulation of substrate—Depending on the pathway and point(s) or blockage, intermediates may also accumulate or minor branches of the pathway may be stimulated (exemplified in galactosima and lysosomal storage diseases)
Decreased end product—As a lack of tyrosinase will lead to a lack of tyrsine, a precursor to melanin, will result in albinsim
Failure to inactivate tissue damaging substrates—Without α-antitrypsin, individuals cannot inactivate neutrophil elastase in their lungs leading to pulmonary emphysema
Defects in receptors and transport systems can occur through a number of mechanisms: failed transport of receptors to the plasma membrane, failure for the protein to be coded, decreased affinity of the substrate—for example. These defects are exemplified in the familial hypercholesterolemia (reduced expression of LDL receptors or defective transport mechanisms) or cystic fibrosis (impaired or unexpressed chloride transporters).
Sickle cell disease is a canonical example of an alteration in the structure (and also function) of a non-enzyme protein. Similarly thalassemias are a result of mutations genes that affect the amount of globin chains the body synthesizes. Disorders that effect collagen (ostogenesis imperfecta), spectrin (hereditary spherocytosis), and dystrophin (muscular dystrophies) are examples of alterations to structural non-enzyme proteins.
Genetic variants may changes the way individuals react to drugs as exemplified by a deficiency in glucose-6-phosphate-dehydrogenase (G6PD); administration of an antimalarial drug will result in severe hemolytic anemia though there are no other signs of disease associated with the genetic variant. Pharmacogenetics is a growing area of genetics that studies the genetic factors that impact drug metabolism and sensitivity.
While several diseases are associated with defects in structural proteins, the text discusses Marfan and Ehlers-Danlos syndromes because of their effects on connective tissues.
Marfan syndrome is most notable for its affect on the skeleton, eyes, and cardiovascular system. It is seen in about 1 in 5000 individuals and is an autosomal dominant disorder. Approximately 15-30% of cases are de novo mutations.
Etiology. It is a result of the extracellular protein fibrillin-1 leading to loss of structural support of microfibril rich connective tissue and activation of transforming growth factor-β (TGF-β) signaling.
Fibrilin is the major structural protein found in microfibrils, which are in the extracellular matrix and provide the scaffolding for elastic fibers to be deposited. Microfibrils are especially abundant in the aorta, ligaments, and ciliary zonules (which support the lenses). Fibrilin has to forms fibrilin-1 (gene: FBN1 on 15q21.1) and fibrilin-2 (gene: FBN2 on 5q23.31). Individual with Marfan syndrome typically carry a missense mutation giving rise to abnormal protein products that inhibit polymerization of fibrilin fibers (a dominant negative effect) or fibrilin content cannot meet strength thresholds for connective tissue, termed haploinsufficiency.
Microfibrils also play a role in sequestering transforming TGF-β this increasing the availability of this cytokine. It hampers smooth muscle development and causes loss of the extracellular matrix (through activation of metalloproteases). It also explains the overgrowth of bones myxoid changes in mitral valves. Support for this schema can be found in affected individuals with without an FBN1 mutation but a gain of function in TGF-β
Clinical features. Loss of support makes mitral vales soft and billowy (floppy valves). Affected individuals typically have mitral regurgitation. The majority of deaths from Marfan syndrome are caused by ruptures of aortic dissections followed by cardiac failure.
Because of the large variance in clinical expression (due likely to the over 600 pathological variant), diagnosis of Marfan syndrome typically requires major involvement of two of the following organ systems: skeletal, cardiovascular, ocular, and skin—along with minor of one of the aforementioned. Treatment typically includes administration of β blockers reduce heart rate and aortic wall stress. Experimental treatments include inhibition of TGF-β action.
Lysosomes have important hydrolytic enzymes that function in an acid environment and a special category of secretory proteins that are destined for intracellular organelles that are processed by the Golgi apparatus. After being translated by the endoplasmic reticulum they undergo attachment of terminal mannose-6-phosphate groups to some of the oligosaccharide side chains that directs segregation of the secretory proteins. Transport vesicles with the receptor bound enzymes are pinched off from the Golgi and fuse with the target lysosome before returning to the Golgi.
Lysosome are fundamentally responsible for the breakdown of macromolecules; derived from autophagy or heterophagy. Defects in the normal function of lysosomes has two major pathological consequences:
Primary accumulation—Catabolism of substrates is incomplete and insoluble intermediate metabolites accumulate with lysosomes, which become large and numerous enough to interfere with normal cell function.
Secondary accumulation—Failure to preform autophagy results in accumulation of polyubiquinated proteins and old/ineffective organelles. Presence of defective mitochondria with poor calcium buffers and abnormal membrane potentials can lead to the generation of ROS or trigger apoptosis.
The are two practical therapies for lysosomal storage disorders: enzyme replacement and substrate reduction. In disorder where the protein is misfolded, molecular chaperone therapy the use of an innocuous exogenous competitive inhibitor of the defective enzyme can act as “folding template,” as is the case for Gaucher disease.
The etiology of lysosomal disorders depends on two interrelated factors (1) the tissues where molecules to be degraded are found and (2) the tissues where degradation occurs. For example, defects in GM1/GM2 gangliosidoses will manifest in neurological symptoms as gangliosides are found in the brain while defects in mucopolysaccharidoses (MPSs) will affect nearly every tissue. Moreover, organs with high phagocytic activity such as the spleen an liver will be enlarged across all lysosomal storage disorders.
Degradation of GM2 gangliosides is accomplished by three different polypeptides encoded by three different genes; together forming hexosaminidase A. The most common pathogenic variants occurs in the α-subunit locus on chromosome 15, which gives rise to Tay-Sachs disease; the disorder is autosomal recessive. Antenatal diagnosis and carrier detection are possible through enzyme assays and genetic testing. Over 100 pathogenic variants have been identified most of which trigger apoptosis via the “unfolded protein” response; protein chaperone therapy has hence emerged as a potential treatment.
Individuals are typically present at 6 months of age with:
Motor incoordination
Mental obtundation
Muscle flaccidity
Blindness
Dementia
A characteristic (but not pathognomonic) cherry-red spot appears in the macula of the eye during the early course of the disease as a result of normal color of the macula choroid contrasted by the pallor of ganglion cells swollen with lysosomes.
Over the course of 1-2 years a complete vegetative state is reached followed by death at 2-3 years. Carriers of a pathogenic variant can be as common as 1 in 30 ashkenazic jewish individuals. The two other forms of GM2 gangliosidosis: β-subunit defects (Sandhoff disease) and GM2 activator deficiency have similar clinical presentations as Tay-Sachs.
Niemann-Pick diseases are caused by accumulation of sphingomyelin in the lysosomes due a deficiency the eponymous catabolic enzyme. The gene for acid sphingomyelinase is located on 11p15.4 and the paternal gene is typically imprinted. Hence, though the disease follow autosomal recessive patterns of inheritance, heterzygotes who inherited a pathogenic allele from their mother may develop the disorder. More than 100 pathogenic variants have been identified and are correlated with severity of deficiency and phenotype.
The enzyme deficiency leads to accumulation of the lipid in lysosomes, particularly in the mononuclear phagocyte system. Staining and electron microscopy confirms that lysosomes are filled with membranous cytoplasmic “zebra” bodies. Lipid-laden phagocytic foam cells accumulate most notably in the spleen—sometimes to 10 times its size—though can be found in the liver, lymph nodes, bone marrow, gastrointestinal tract, and lungs. The disorder affects all parts of the nervous system. In the brain gyri and sulci are shrunken and widened, respectively. Vacuolation and ballooning of neurons causes widespread cell death and loss of brain matter over time.
Individuals with the type A disorder may have symptoms at birth but present invariably by 6 moths of age with:
Protuberant abdomen (hepatosplenomegaly)
Failure to thrive
Vomiting
Fever
Generalized lymphadenopahty
Progressive degeneration of psychomotor function
Culminating in death within the first or second year of life. Individuals with the type B disorder have organomegaly but do not suffer neurological symptoms and typically survive into adulthood. Diagnosis is established though assay of sphingomyelinase extracted from the liver or bone marrow. Genetic testing can confirm the disorder as well as carrier status.
Though once thought related to Nimann-Pick types A & B, type C is caused by pathogenic variants in NPC1 and NPC2. Type C is more common that both A & B and may present as hydrops fetalis, stillbrith, or neonatal hepatitis. A chronic form presents as progressive neurological damage (ataxia, vertical supranuclear gaze palsy, dystonia, dysarthia, and psychomotor regression).
NPC1 and NPC2 are transport proteins that move free cholesterol from the lysosomes to the cytoplasm. Defects in membrane bound NPC1 accounts for 95% of all cases and the rest is accounted for in the soluable NPC2.
There are three clinical subtypes of Gaucher diseases all of which are a result of mutations in the gene that codes for glucocerebrodisease, an enzyme that cleaves the glucose residue from ceramide. Glycocerebrosides are from the continuous breakdown of glycolipids; accumulation affects phagocytes most notably.
Type I—Accounts for 99% of all cases. Storage burden affects mononuclear phagocytes thorough the body save the brain; splenic and skeletal dysfunction are characteristic of the disorder; and glucocerebrodisease is detectable though reduced. Affected individuals have a mildly or moderately shortened life span.
Type II—Also called acute neuronopathic Gaucher disease is characterized by progressive deterioration of the central nervous system in infancy. There is no detectable activity of glucocerebrodisease.
Type III—Adolescents or young adults will present with both systematic and central nervous system dysfunction.
Normal growth and differentiation is regulated by two classes of genes: tumor suppressor genes and proto-ocogenes. The vast majority of cancer causing mutations occur in somatic cells and are not passed in the germ line though some are. Most familial cancers are passed through autosomal dominant inheritance.
Complex multigenic disorders occur when many polymorphisms (variants in the alleles of gene) are co-inherited. Different polymorphisms may have variable penetrance and contribution to the overall phenotype. Moreover, they may contribute to more than one disease or may be highly specific. Environmental factors may also play an important role in the expression of complex traits. Determining modes of disease inheritance of such disorders may be challenging.
The most basic tool of cytogeneticits is karyotyping. There are a variety of different staining methods but celles are arrested during metaphase and the chromosomes and their bands can be analyzed. Karyotypes describe the number, sex chromosomes, and any anomalies (e.g. 46,XX or 47,XY,+21). The short arm is denoted with p and long with q. A specific band (used in characterization of disorders) will be denoted by the chromosome, the arm, the band, and subband (e.g. 21q11.1).
Errors in meiosis and mitosis that result in aneuploidy (not an integer multiple of the haploid number) are nondisjunction and anaphase lag. The former results in two gametes: one with an extra chromosome and one that is missing a chromosme—fertilization results in trisomic and monosomic zygotes, respectively. In the latter, a homologous chromosome (during meiosis) or chromatid (during mitosis) lags during anaphase and is left outside of the nucleus resulting one normal cell and a cell with monosomy. Typically monosomy of autosomal chromosomes do not permit live births.
Moasicism, two or more cell population with different chromosomal complement in the same individual, can arise from mitotic errors in early development occurring during cleavage of fertilized ovum or in somatic cells. Such cleavage may result in a daughter cell receiving one sex chromosome while the other receives three leading to a 45, X/47, XXX mosaic of cells and a variant of Turner syndrome.
There are a number of other chromosome aberrations that typically a result of breakage and errors in repair or unbalanced cross-over:
Deletion—A break, repair, and loss of material around the breakage point may be denoted as 46, XY, del(16)(p11.2p13.1), the material between 11.2 and 13.1 on the p arm of chromosome was deleted.
Ring chromosome—Breakage of a chromosome at the ends of may result in the fusion of the two ends to from a ring, denoted as r(14).
Inversion—An inversion of a part of the chromosome that includes the centromere is called pericentric while paracentric is used to refer to inversions that don’t include the centromere.
Isochromosome—This occurs with an arm is lost and the remaining arm is duplicated resulting in a chromosome with to p arms, for example; this is associated with trisomy for duplicated arm and monsomy for the lost arm.
Translocation
Balanced reciprocal translocation refers to breaks and cross fusion in two non-homologous chromosomes without loss of genetic material, which may be denoted as 46,XX,t(2;5)(q31;p14). This type of translocation is not likely to result in a clinical presentation as no genetic material is lost. However, progeny is likely to be effected because a fertilized gamete will have unbalanced genetic material.
Robertsonian translocation refers to the breakage and fusion of two acrocentric. Loss of the p arms is normal an usually does not have highly deleterious affects as that DNA is typically redundant (ribosomal RNA). A 45, XY, t(14; 21) is not likely to have a clinical presentation but all progeny (e.g. 46, XY, t(14; 21)) will express trisomy 21.
The most common cause of trisomy 21 is nondisjunction during meiosis though about 4% of cases are caused by robertsonian translocation. Likely hood of trisomy is positively correlated with maternal age (1 in 1550 among mothers under age 20 and 1 in 25 among mothers over 45). In cases of mosaicism and robertsonian translocation (1% of all cases), maternal age does not affect risk.
Individuals with trisomy 21 typically have the following features at birth:
Flat facial profile
Oblique palpebral fissures
Epicanthic folds (fold that covers inner corner of the eye)
Single transverse palmer crease
Hypotonia
Umbilical hernia
Other clinical features that are important considerations for individuals and families later in life are:
40% of affected individuals have congenital heart disease.
A 10 to 20-fold increased risk for acute leukemia (most commonly magakaryoblaskic).
Neuropathologic changes after the age of 40 (e.g. Alzheimer disease)
Abnormal immune responses and predispositions for serious infections.
The molecular basis of disease of trisomy 21 is unknown. Only about 35% of the genes on chromosome 21 are overexpressed by 150%. Moreover, a number of miRNA genes have been identified to be on chromosome 21 that may be related to other parts of the genome. Prenatal diagnosis of trisomy can now occur through a noninvasive maternal blood test to identification of cfDNA (circulating free DNA).
Also known as Edwards syndrome, affected individuals typically have short necks; low set, rotated, and unfurled ears; overlapping fingers; renal malformation; congenital heart defects; a prominent occiput; “rocker-bottom feet”; limited hip abduction; and micrognathia. Survival is not common past the first year of life.
Also called Patau syndrome, affected individuals have microcephaly and limited cognitive function; cleft lip and palate; cardiac and renal defects; umbilical hernia; rocker-bottom feet; polydactylyl; and microphthalmia. It is relatively uncommon and survival is not common past the first year of life.
The syndrome is fairly common (1 in 4000) and can manifest with a variety of different features: congenital heart defects, abnormalities of the palate, facial dysmorphism, developmental delay, or a variable degree of T-cell immunodeficiency or hypocalcemia. Recent studies have identified that individuals with 22q11.2 deletion are at a high risk for mental health disorders such as schizophrenia and bipolar disorder. Diagnosis requires detection of the deletion by FISH. Some genes of the deleted region have been linked to the expression of the facial features though the molecular basis for the disorder is not well understood.
Disease associated with aberrations of the sex chromosomes is much more common and better tolerated than those of autosomes—likely because of X chromosome inactivation and the small amount of genetic material on the Y chromosome. In general, sex chromosome disorders are subtle, relate to sexual development and fertility and are usually diagnosed at puberty rather than at birth. X inactivation occurs randomly in the cells of the blastocyst around the 5th day of embryonic development. Once inactive the same chromosome will remain inactive in all its future daughter cells. However, the entire chromosome is not inactivated. Hence, females need two X chromosomes for normal development (exemplified by the characterization of 45,X or Turner syndrome).
47,XXY is the most common disorder involving the sex chromosomes affecting 1 in 660 live births. It is generally not diagnosed before puberty as the disorder typically only affects secondary sexual characteristics and and to a minor extent cognitive function.
Individuals are eunuchoid body habitus (tall, underweight, arm span exceeds height by at least 5cm, longer legs); have small atrophic testes and penis; lack a deep voice, beard, and male pubic hair; and potentially gynecomasita (increased breast tissue in males) may be present. Individuals are also at a greater risk for type 2 diabetes and metabolic syndrome as well as osteoporosis and fractures. Follicle-stimulating hormone and plasma gonadotropin concentrations are consistently elevated. Fertility is greatly affected and testicular tubules are especially implicated.
Though all but one X-chromosome undergoes inactivation, the portions of the X-chromosomes that are not inactivated are thus “overexpressed” leading to hypogonadism. Additionally, in individuals 47,XXY the X-chromosome with the least CAG repeats in the androgen receptor gene is preferentially inactivated leading to increased sensitivity to the hormone exacerbating hypogonadism and other aspects of the phenotype.
Tuner syndrome affects approximately 1 in 2500 live births. Most affected individuals are missing one X-chromosome while the rest have structural anomalies in the X-chromosome (e.g. isochromosomes or ring chromosomes) or display mosaicism for the disorder (45,X/46,XX; 45,X/46,XY; 45,X/47,XXX; or 45,X/46,X,i(X)(q10)).
The most highly expressive individuals are diagnosed at birth given presentation of edema of the hands and feet (due to lymph stasis) and sometimes swelling in the neck (due to distended lymphatic channels). Swelling subsides with development but often leaves neck webbing and looseness of the skin at the back of neck. Congenital heart disease is common among affected individuals and is a major contributor to mortality. Coacrtation of the aorta and bicuspid aortic valve are seen most frequently.
Individuals typically present to the clinic with failure to develop secondary sexual characteristics, short stature, and amenorrhea (no menstrual cycle). About half of affected individuals develop antibodies that interact with the thyroid gland which can develop into hypothyroidism. Patients also are at higher risk for glucose intolerance, obesity, and insulin resistance. The latter most is of clinical importance because treatment for short stature with growth hormones increases insulin resistance.
Though the molecular basis for Turner syndrome is not well understood some research has shown that the absence of the second X-chromosome in fetal development leads to accelerated loss of oocytes and is completed by age 2. In this sense “menopause occurs before menarche” leaving the ovaries reduced to atrophic fibrous strands without any ova or follicles (commonly called streak ovaries). Additionally the short stature can be explained by lack of a second copy of the short stature homeobox (SHOX) gene.
Diseases that do not follow classical mendelian genetic inheritance patterns can have 4 major molecular bases:
Trinucleotide-repeat mutations
Mutations in mtDNA
Genetic imprinting
Gonadal mosaicsim
The molecular basis of disease for as many as 40 disorders are a result of trinucleotide-repeats. These sequences are usually rich in G and C nucleotides. The mechanisms of expansion varies between diseases (expansion occurs during oogenesis in the case of fragile X syndrome while expansion occurs during spermatogenesis in the case of Huntington diseases). These disorders have three key mechanisms of diseases:
Loss of function—Transcription silencing prevents gene expression as is the case with fragile X syndrome.
Toxic gain of function—Expansion in coding regions can cause significant alterations in protein structure as is the case in Huntington disease and pinocerebellar ataxis.
Toxic gain of function mediated by mRNA
The molecular basis of disease for expansions that affect protein coding regions is distinct from those that affect noncoding regions. The former typically involve repeats of CAG, which codes for glutamine, hence earning the characterization of “polyglutamine diseases.” Such diseases may be dominant negative—interfering with the function of other normal proteins—or gain a pathogenic function. Nonetheless, the proteins tend to aggregate and form many large intracellular inclusions, which may suppress transcription, trigger cell stress leading to apoptosis, or cause metabolic dysfunction. Yet such inclusions may be protective sequestrations of toxic protein activity.
is the most common genetic cause of diminished cognitive function after trisomy 21 affecting 1 in 1550 males and 1 in 8000 females. The disease caused by various trinucelotide expansions (usually containing cytosine and guanine) in the familia mental retardation-1 (FMR1) gene.
Low IQ: range 20-60
Long face, ears (everted), and mandible
Macro-orchidism (large testicles) common in 90% of cases
Though it is and X-linked disease, its patterns of inheritance have a number of unique traits:
Carrier males—Males can be identified as obligate carrier of the disorder though pedigree analysis though they do not present a clinical nor cytogenetic traits.
Affected females—30-50% of carrier females will manifest the phenotype.
Risk of phenotypic effects—Subsequent generations of transmitting males are much more likely to express the phenotype than are other males of the transmitting male’s generation.
Anticipation—Clinical features worsen with successive generations as the mutation expands and becomes increasingly deleterious.
FMR-1 is located on Xq27.3 and its tandem repeats occur in the 5′ UTR of the mRNA transcript. In the normal population that average number of repeats is 29 and ranges from 6 to 55. Transmitting males and carrier females have between 55 to 200 repeats termed premutations. A full mutation is greater that 200 repeats. The difference in the number of repeats between carrier males and his progeny does not have a large variance while the number of repeats tends to increase between carrier females and her progeny. Hence, trinucleotide expansion in this gene appears to occur during oogenesis.
The silencing of FMR-1 is likely due to excessive methylation of the locus and formation of heterochromatid around the gene effectively silencing transcription. The protein coded by FMR-1, FMRP is typically expressed in the testis and brain and is likely to be involved in regulation of the transport of mRNA to dendrites and translation of the transcripts.