Single Gene Disorders with non Mendelian inheritance
Disorders of trinucleotide repeat mutations
- Normally, a codon is triplet (trinucleotide).
- In the normal people, the number of repeat of a particular triplet codon is small (e.g. for CGG it is 5-50 and CGG triplet codon can be repeated, at a stretch, 5-50 times).
- In trinucleotide repeat mutations, this nucleotide sequence undergoes amplification (expansion of a stretch of nucleotide) and the same sequence is repeated many times in the genome.
- Initially there is a small increase in trinucleotide copy number (e.g. 55-200 of CGG in fragile X syndrome) which is referred to as premutation. In premutation the disease is not manifested and the person acts as carrier.
- If the expansion of repeats goes above a threshold level (e.g. > 200 of CGG repeat in fragile X-syndrome), gene function is impaired and the disease is manifested.
- The repeat may be located in
- Coding region â Huntington disease, Spinobulbar muscular atrophy.
- Non-coding region â Fragile-X syndrome, myotonic dystrophy)
- Anticipation is a phenomenon where by the symptoms of genetic disorders become apparent at an earlier age as it is passed to next generation.
- In triplet nucleotide repeat mutation, the DNA fragment is unstable and tends to expand further during cell division
- So, in successive generations the expanded repeat increases and the manifestations of disease may worsen or to be observed at an earlier age; this phenomenon is referred to as anticipation.
Fragile - X syndrome
- Fragile - X syndrome is the prototype of diseases in which the mutation is characterized by a long repeating sequence of three nucleotides.
- In fragile X syndrome, trinucleotide repeat mutation involves CGG on non coding region.
- Clinical features of fragile - X syndrome
- Mental retardation
- Long face with large mandible
- Hyperextensible joint
- Mitral valve prolapse
- Large everted ears
- Large testis (macro-orchidism)
- High arched palate
- Fragile X syndrome is the second most common cause of mental retardation, after Downâs syndrome.
- Human inherits two copies of each gene, i.e. two alleles, from homologous maternal and paternal chromosomes.
- There is no functional difference between the genes derived from mother or the father.
- But, with respect to some genes, there are functional differences between the paternal gene and maternal gene.
- These differences result from an epigenetic process, called genomic imprinting.
- In most cases, genomic imprinting selectively inactivates either the maternal or paternal allele.
- Maternal genomic imprinting
- Selective inactivation of maternal allele.
- Example is Angelman syndrome.
- Paternal genomic imprinting
- Selective inactivation of paternal allele.
- Example is Prader - Willi syndrome.
Prader Willi Syndrome
Deletion occurs exclusively on paternal chromosome 15 (deletion of band q 12 in long arm of chromosome 15)
- Diminished fetal activity
- Mental retardation
- Short stature
- Hypogonadotropic hypogonadism
Deletion occurs exclusively on maternal chromosome 15
- Mental retardation
- Inappropriate laughter (Happy puppets)
- Germline mosaicism results from a mutation that occurs post zygotically during early embryonic development. In these a portion of the egg or sperm cells of a parent carries the mutation.
- Because the mutation affects only cells destined to form the gonads the gametes carry the mutation but somatic cells of the individual are completely normal.
- A phenotypically normal parent who has germ line mosaicism can transmit the disease causing mutation to the offspring through the mutant gamete.
- Because the progenitor cells of the gamete carry the mutation there is a definite possibility that more than one child of such a parent would be affected.
- Obviously, the likelihood of such an occurrence depends on the proportion of germ cells carrying the mutation.
Clinical Syndromes of Mitochondrial Disease
- Chronic progressive external ophthalmoplegia (CPEO)
- Kearns-Sayre -syndrome (KSS)
- Pearson syndrome
- Neurogenic weakness with ataxia and retinitis pigmentosa (NARP)
- Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)
- Myoclonic epilepsy with ragged-red fibers (MERRF)
- Leber hereditary optic neuropathy (LHON)