Sex-linked and Nontraditional Modes of Inheritance Chapter 5 Sex-linked and Nontraditional Modes of Inheritance

X Inactivation Inactivation of one X-chromosome of female Tunesian wedge-faced calico X Inactivation Inactivation of one X-chromosome of female

X Inactivation evidence of X inactivation Causes X Inactivation Tunesian wedge-faced calico X Inactivation evidence of X inactivation female mice → dappled coloring of fur female calico cat → black and orange patches of fur albinism (a X-linked recessive disease): female heterozygotes → pigment patches two different variants of enzymes in famales Barr bodies (inactive X-chromosome) Causes mRNA of XIST gene (X inactivation gene of X chromosome) due to heavy methylation of CG repeats of X chromosome due to histone acetylation

X-linked Recessive Inheritance hemophilia A, Duchenne muscular dystrophy, fragile X syndrome, red-green color blindness Charateristics heterozygote female: 50% of the normal level of gene product → a normal phenotype dominant or recessive : only to female hemizygous male → abnormal skipped generation : affected father → carrier daughter → affected grandson Manifesting heterozygotes (in female) : inactivation of most normal X chromosome (eg. 5% of female hemophilia A)

Inheritance of an X-linked Recessive Trait X-linked Recessive Inheritance Inheritance of an X-linked Recessive Trait

Punnett Square Representations of X-linked Recessive Inheritance

Additional Examples of X-Linked Recessive Disorders X-linked Recessive Inheritance Additional Examples of X-Linked Recessive Disorders

X-linked Dominant Inheritance hypophosphatemic rickets, incontinentia pigment type 1, Rett syndrome Charateristics heterozygous female: milder expression of X-linked dominant traits than hemizygous male twice common in females no father-son transmission

X-linked Dominant Inheritance Pedigree demonstrating the inheritance of an X-linked dominant trait

Comparison of the Major Attributes of X-Linked Dominant and X-Linked Recessive Inheritance Patterns

Y-linked Inheritance Pedigree demonstrating the inheritance of a Y-linked trait. 

Mitochondrial Inheritance Mitochondrial genes (16,569 bp): 2 rRNAs, 22 tRNAs, 13 polypeptides for oxidative phosphorylation lack of DNA repair mechanism and damage from free radicals produced during the oxidative phosphorylation → 10 times higher mutation rate than nuclear DNA organs with large ATP requirement (high threshold) → seriously affected Characteristics inherited through the maternal line heteroplasmy by replicative segregation (via chance variation or a selective advantage)

Human mitochondrial DNA Mitochondrial Inheritance Human mitochondrial DNA

Mitochondrial Inheritance A pedigree showing the inheritance of a disease caused by a mitochondrial DNA mutation.

Mitochondrial Inheritance Missense mutations of protein-coding genes: Leber hereditary optic neuropathy (LHON) Single-base mutations of tRNA genes: myoclonic epilepsy with ragged-red fiber disease (MERRF), mitochondrial encephalomyophathy and strokelike episodes (MELAS) Duplication and deletion: Kearns-sayre disease, chronic progressive external ophthalinoplegia (CPEO), Pearson syndrome, diabetes, deafness, Alzheimer disease

Genomic Imprinting Genomic Imprinting differential activation of genes, depending on the parent from which they are inherited eg. a deletion on the long arm of chromosome 15 Prader-Willi syndrome: from father, a protein involved in ubiquitin-mediated protein degradation Angelman syndrome: from mother, a small nuclear riboprotein expressed in the brain (SNRPN) the degree of methylation of the gene ↔ transcriptional inactivation

Genomic Imprinting Genomic Imprinting

Genomic Imprinting Genomic Imprinting Schematic of the organization of several imprinted genes on chromosome 11p15.5 that are involved in the pathogenesis of Beckwith-Wiedemann syndrome and Russell-Silver syndrome.

Anticipation Anticipation earlier onset and/or more severe expression in more recent generation of a pedigree eg. Myotonic dystrophy AD, progressive muscle deterioration, pleiotropic, locus heterogeneity expanded CTG repeats in 3´ untranslated region of DMPK (myotonic dystrophy protein kinase) in  19q (5-30: normal, 50-100: mildly affected, >100: severe) expansion of CCTG in 3´ untranslated region of ZNF9 gene on chromosome 3q21 eg.  Huntington’s disease: CAG repeat, fragile X syndrome: CGG repeat, spinocerebellar ataxia type I: CAG repeat

Anticipation Anticipation A three-generation family affected with myotonic dystrophy Myotonic dystrophy pedigree illustrating anticipation

Diseases Associated with Repeat Expansions Anticipation Diseases Associated with Repeat Expansions Disease Description Repeat Sequence Normal Range; Disease Range Parent in Whom Expansion Usually Occurs Location of Expansion Category 1 Huntington disease Loss of motor control, dementia, affective disorder CAG 6-34; 36-121 More often through father Exon Spinal and bulbar muscular atrophy Adult-onset motor-neuron disease associated with androgen insensitivity 9-36; 38-62 Spinocerebellar ataxia type 1 Progressive ataxia, dysarthria, dysmetria 6-39; 40-82 ataxia type 2 Progressive ataxia, dysarthria 15-24; 32-200 - ataxia type 3 (Machado-Joseph disease) Dystonia, distal muscular atrophy, ataxia, external ophthalmoplegia 13-36; 61-84 ataxia type 6 Progressive ataxia, dysarthria, nystagmus 4-19; 20-33 ataxia type 7 Progressive ataxia, dysarthria, retinal degeneration 4-35; 37-306 ataxia type 17 Progressive ataxia, dementia, bradykinesia, dysmetria 25-42; 47-63 Dentatorubral- pallidoluysian atrophy (Haw River syndrome) Cerebellar atrophy, ataxia, myoclonic epilepsy, choreoathetosis, dementia 7-34; 49-88

Anticipation

Fragile X Syndrome Characteristics 40% of all X-linked mental retardation 1/4,000 male (80% penetrance), 1/8,000 female (30% penetrance) larger ears and long face, hypermobile joints, macroorchidism A perplexing pattern of X-chromosome-mediated inheritance (Sherman paradox) normal transmitting males (NTM) Mothers of NTM (carrier) had a much lower proportion of affected sons than did daughters of NTM (carrier). Daughters of NTM (carrier, not affected) produced affected sons.

Inheritance of Typical X-linked Genetic Diseases and Fragile X Syndrome Typical X-linked disease Fragile X syndrome NTM 5-9% 16-40% 16-50%

Fragile X Syndrome Causes DNA diagnosis for X fragile syndrome expansion and methylation of CGG repeats in 5´ region of FMR1 gene expansion and methylation of CGG repeats 5´ region of FRAXE gene (FMR2) DNA diagnosis for X fragile syndrome CGG expansion and methylation degree in FMR1 or FRAXE cytogenetic analysis of the long arm of the X chromosome

Hemophilia A

Duchenne muscular dystrophy

Fragile X syndrome

Hypophosphatemic rickets Cause by a mutation in the fibroblast growth factor 23 (FGF23) X-linked dominant Symptoms excessive loss of phosphate in the urine poorly formed bones (rickets), bone pain, and tooth abscesses. Diagnosis Blood tests reveal low levels of phosphate (hypophosphatemia) abnormal levels of vitamin D Treatment increasing phosphate intake and high doses of vitamin D

Incontinentia pigmenti Cause By a deletion of exons 4 through 10 of IKBKG (Inhibitor of Kappa Light Polypeptide Gene Enhancer in B Cells Gamma Kinase) Symptoms Characteristic skin lesions, Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails Retinal defects, cognitive delays/mental retardation Diagnosis molecular genetic testing of IKBKG (NEMO)

Rett syndrome Cause Symptoms Diagnosis By sporadic mutations in the gene MECP2 (methyl CpG binding protein 2) located on the X chromosome Symptoms a deceleration of the rate of head growth and small hands and feet. cognitive impairment Diagnosis molecular genetic testing of MECP2 mutations

Leber’s hereditary optic neuropathy (LHON) Cause mutations at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes : complex I (NADH dehydrogenase) of the oxidative phosphorylation chain in mitochondria 1:30,000 to 1:50,000 in Europe Symptoms degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision affecting predominantly young adult males only transmitted through the mother Diagnosis and Treatments a neuro-ophthalmological evaluation and/or blood testing for DNA assessment avoiding optic nerve toxins no convincing treatments yet

Myoclonic epilepsy with ragged-red fiber disease (MERRF) Cause by a maternally-inherited mutation at position 8344 in the mitochondrial genome : disruption of the mitochondrial gene for tRNA-Lys disrupting synthesis of proteins essential for oxidative phosphorylation Symptoms progressive myoclonic epilepsy clumps of diseased mitochondria accumulate in the subsarcolemmal region of the muscle fiber and appear as "ragged-red fibers" when muscle is stained with modified Gomori trichrome stain short stature Diagnosis and Treatments blood testing for DNA assessment no convincing treatments yet

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) Cause mutations in the MT-ND1(over 80%), MT-ND5, MT-TH, MT-TL1, and MT-TV mitochondrial genes Symptoms muscle weakness, altered consciousness, vision abnormalities, seizures, and severe headaches Repeated stroke-like episodes lactic acidosis : vomiting, abdominal pain, fatigue, muscle weakness, and difficulty breathing Diagnosis and Treatments molecular diagnosis, no known treatment (managements according to symptoms)

Kearns-Sayre syndrome (KSS) Cause by a 5,000 base deletion in the mitochondrial DNA Heteroplasmic, not maternally inherited (sporadic) start before the age of 20 Symptoms vision loss, dysphagia, proximal weakness, hearing loss, cerebellar ataxia and cardiac conduction defects Diagnosis and Treatments molecular diagnosis no cures, only palliative medications

Chronic progressive external ophthalmoplegia (CPEO) Cause by deletions or mutations to segments of mtDNA lead to defective function of oxidative phosphorylation Symptoms ptosis or drooping lids some muscle weakness Diagnosis and Treatments muscle biopsy, molecular tests no defined treatment surgery to raise the lids

Pearson syndrome Cause Symptoms Diagnosis and Treatments a deletion in mitochondrial DNA Symptoms Sideroblastic anemia of childhood Pancytopenia Exocrine pancreatic failure Diagnosis and Treatments Bone marrow examination reveals ringed sideroblasts, normoblasts with excessive deposits of iron in mitochondria detected by iron stains. blood testing for DNA assessment no cures