Please enable JavaScript.
Coggle requires JavaScript to display documents.
Sex-linked modes of inheritance - Coggle Diagram
Sex-linked modes of inheritance
Definitions
Anticipation
.
Earlier age-of-onset of some genetic diaseses in more recent generations of families.
Imprinting
Some genes are expressed only on paternally transmitted chromosomes and others are expressed only on maternally transmitted chromosomes.
Heteroplasmy
Each cell contains a population of mtDNA molecules, a single celle can harbor some molecules that have an mtDNA mutation and other molecules that do not. It is a important cause of variable expression in mitochondrial diseases.
Imprinting
The normal individual would have only one transcriptionally active copy of the gene. E.g., an allele transmitted by the mother would be inactive, and the same allele transmitted by the father would be active. The process of gene silencing is known as imprinting.
Uniparental disomy
An individual inherits two copies of a chromosome from one parent and nondescripts from the other. E.g. when two copies of the maternal chromosome 15 are inherited, PWS results because no active paternal genes are present in the critical region.
Mitochondrial diseases
Organ systems with large ATP requirements and high thresholds tend to be the ones most seriously affected by mitochondrial diseases.
E.g. CNS consumes about 20% of the body's ATP production and therefore is often affected by mtDNA mutations.
Myoclonic epilepsy with ragged-red-fiber syndrom (MERRF)
Single-base mutations in a tRNA gene.
Epilepsy, dementhia, ataxia (uncoordinated muscle movement), myopathy (muscle disease).
MERRF is characterized by
heteroplastic mtDNA
, is thus highly variable in its expression.
Mitochondrial encephalomyopathy and stroke-like episodes (MELAS)
Single gene mutation in a tRNA gene.
Heteroplasmic, highly variable in expression.
Common human diseases are also associated with mitochondrial mutations: T2DM, some cases of Alzheimers disease.
X-linked
X-linked recessive
Characterized by an absence of father-son transmission, skipped generations when genes are passed through female carriers.
Hemophilia A
Mutations in the gene encodes clotting factor VII.
Males is affected
Hemarthroses (bleeding into the joints): ankles, knees, hips, elbows. Painful, repeated episodes can lead to destruction of the synovium and diminish joint function. ICH.
Severity: variable, correlated with the level of factor VII. Severe: <1% normal function, frequent bleeding episodes. Moderate: 5% normal function. Mild: 5-30%, bleeding after a surgery, severe trauma.
Administration: factor VII. Prophylactic factor VII in severe hemophilia preventing loss of joint function.
Hemophilia B
Deficiency of clotting factor IX.
(Von Willebrand disease is an autosomal dominant disorder.It is a carrier protein for factor VII, binds to platelets and damaged blood vesse endothelium, thus promoting the adhesion of platelets to damaged vessel walls.)
Duchenne muscular dystrophy
Clinic: progressiv weakness and loss of muscle. Symptoms is seen before age of 5; unusual clumsiness, muscle weakness. Pseudohypertrophy of the calves (
result of infiltration of muscle by fat and connective tissue
). All skeletal muscle degenerates and patients are
confined to a wheelchair by 11 years of age (<11).
Heart and respiratory muscles become impaired; death usually results from respiratory or cardiac failure. Survival > 25 years is uncommon.
Paraclinic: CK leaks out as muscle cells die. Elevated > 20 times above the upper limit. Electromyografy: reduced action potentials. Muscle biopsy.
Affects male.
Becker muscular dystrophy
Less svare than the Duchenne form.
Progression is much slower, onset of 11 years of age.
Confined to wheelchair >11.
Less common than DMD.
Red-green colorblindness
X-linked dominant
Characterized by a person need inherit only a single copy of an X-linked dominant disease gene to manifest the disorder.
Hypophosphatemic rickets
A disease in which the kidneys are impaired in their ability to reabsorb phosfate. Abnormal ossification.
Rett syndrome
Neurodevelopmental disorder, primarily females are affected.
Autistic behavior, intellectual disability, seizures, gait ataxia.
X-inactivation effects the severity.
X- inactivation
Dosage compensation:
gene on the X-chromosome is present in equal quantities in males and females.
Lyon hypothèses
: one chromosome in each cell is randomly inactivated early in the embryonic development of females. This ensures that females, who have two copies of X-chromosome, will produce X-linked gene products in quantities roughly similar to those produced in males (dosage compensation)
Supported by cytogenetic evidence: Barr bodies.
Random and fixed
: Permanent for all somatic cells in the female, but inactive X chromosome must later become reactivated in the females gremlin so that each of her egg cells will receive one active copy of the X chromosome.
Incomplete: 1
5% of the genes on X-chromosome escape inactivation. Tip of the short and long arm.
X-linked recessiv ocular albinism
Lack of melanin production int he retina, ocular problems such as nystagmus. Decreased visual acuity.
Male:
uniform lack of melanin in their retina
Female:
heterozygotes, alternating patches of pigmented and non-pigmented tissue.
Females are X-chromosome mosaics.
Imprinted diseases
Transcriptionally silenced genes are said to be imprented.
Prader-Willi Syndrome
Deletion in chromosome 15 inherited from the father, the child manifests PWS. Features include short stature, hypotonia (poor muscle tone), small hands and feet, obesity, mild to moderate intellectual disability, hypogonadism.
Angelman syndrome
If the deletion is inherited from the mother, the child develops AS. Severe intellectual disability, seizures, ataxic gait.
The gene responsible for AS encodes a protein involved in ubiquitin-mediated protein degradation during brain development.
There is only one gene that is active on the inherited chromosome 15. If the one chromosome is lost through a chromosome deletion, the no gene product is produced at all, and disease results.
Uniparental disomy
De novo deletion
Etiology of genetic alterations
de novo-deletion
: normal chromosom in father and mother, new mutation in the Childs chromosome.
uniparental disomi
- inherited two copies of the chromosome from the same parent. Two chromosome 15 from mother will result in PW-syndrom. Who chromosome 15 from the father will result in Angedlman-syndrome.
Angelman syndrom (Happy puppet syndrome)
Neurodeveloopmental milestones
Intellectual disability
Severe speech/language delays
Ataxia
Episodes of spontaneous laughter
>80%
Microcephaly
Seizures
<80%
Wide mouth
Widely spaced teeth
Hypopigmentation, light hair
Uplifted flexed arm position
Abnormal sleep-awake cycles
Fascination to water
Beckwith-Wiedemann Syndrome
(up-regulation of IGF2)
Overgrowth condition + increased predisposition to cancer.
Recognizable at birth because of large size for gestational age, neonatal hypoglycemia, a large tongue, creases on the ear lobe, omphalocele.
Increased risk for developing Wilms tumor and hepatoblastoma.
Uniparental disomy on chromosome 11.
Two copies inherited from the father and no copy from the mother.
imprinted generegion encodes
Insuline like growth factor, ILGF2
is normally inactive in the maternally transmitted chromosome and active in the paternally transmitted chromosome. E.g. two copies of the paternal chromosome or the loss of imprinting on the maternal copy, IGF2 gene is present in double dose.
Silver-Russel Syndrome (down-regulation of IGF2)
Loss of methylation of the gene that encodes for IGF2 and diminishes growth. Growth retardation, short stature, leg length discrepancy, small triangular-shaped-face.
Fragile X-syndrome
(X-linked, repeat disorder)
Characterized by a distinctive facial appearance, with large ears and long face, hypermobile joints, macroorchidism in postpubertal males.
The degree of intellectual disability tends to be milder and more variable in females than in males.
Lower degree of penetrance in females, variability in expression, reflects variation in patterns of X inactivation (i.e. the percentage of active X chromosomes that carry the disease-causing mutation).
When female offspring transmit the disease-causing gene, FMR1, to their offspring, there is sometimes an expansion from the permutation of 50 to 200 repeats to the full mutation of more than 200 repeats. These expansions do not occur in male transmission.
Males with the permutation do not have daughters with fragile-X syndrome because expansion to the full mutation occurs only in female transmission.
Highest mRNA production of the gene are in the brain. mRNA production is elevated in those with permutations, mRNA accumulates in the nucleus and has toxic effects. In contrast, those with full mutations have no FMR1 mRNA in their cells, indicating no transcription of the gene.