Single Gene Disorders with non-classic Inheritance

Single Gene Disorders with non-classic Inheritance
They fall into four categories: Diseases caused by
1.Trinucleotide repeat mutation
2.Mutation in mitochondrial genes
3.Genomic imprinting
4.Gonadal mosaicism

Single Gene Disorders with non-classic Inheritance
They fall into four categories: Diseases caused by
1.Trinucleotide repeat mutation
2.Mutation in mitochondrial genes
3.Genomic imprinting
4.Gonadal mosaicism

Diseases Caused by
Trinucleotide-Repeat Mutations
• Expansion of trineuclotide repeats is an important genetic cause of human disease, particularly neurodegenerative disordersfirst recognised in 1991
• Till now there are 40 diseases under this category

Diseases Caused by Trinucleotide-Repeat Mutations
• Associated with the expansion of trinucleotides in the genome
• These trinucleotides usually share the G and C
• This makes DNA unstable, and may impair gene function
• Expansion depends strongly on the sex of the transmitting parent
– Fragile X syndrome: Expansions occur during oogenesis
– Huntington disease: Expansions occur during spermatogenesis
Table 5-8 Examples of Trinucleotide-Repeat Disorders

Diseases Caused by Trinucleotide-Repeat Mutations
There are three mechanisms by which unstable repeats cause diseases:
•Loss of function of the affected gene - the repeats are generally in non-coding part of the gene
•A toxic gain of function by alterations of protein structure – the repeats are in the coding regions of the genes
• Huntington disease and
• Spinocerebellar ataxia
•A toxic gain of function mediated by mRNA: noncoding parts of the gene are affected
• fragile X tremor-ataxia syndrome

Fragile X Syndrome and
Fragile X Tremor/Ataxia
• 1 in 1550 for affected males and
• 1 in 8000 for affected females
• FMR1 gene
• CGG repeats:
• In the normal population ranging from 6 to 55 (average, 29)
• Normal transmitting males and carrier females 55 to 200 repeats – premutations
• Affected individuals: 200 to 4000 repeats -full mutations

• Anticipation: Clinical features of fragile X syndrome worsen with each successive generation - as it is transmitted from a man to his grandsons and great-grandsons
Fragile X Syndrome and
Fragile X Tremor/Ataxia
In fragile X syndrome:
Clinical features:
•Males are mentally retarded, IQ 20 to 60
•Long face
•Large mandible
•Large everted ears and
•Large testicles (macro-orchidism)
•Hyperextensible joints

Mutations in Mitochondrial Genes — Leber Hereditary Optic Neuropathy
• A feature unique to mtDNA is maternal inheritance
• Human mtDNA contains 37 genes
• 22 for tRNA
• 2 for rRNA
• The remaining 13 genes encode subunits of the respiratory chain enzymes
• Hence, mutations affecting these genes exert their deleterious effects primarily on the organs most dependent on oxidative phosphorylation
– CNS
– Skeletal muscle,
– Cardiac muscle
– Liver, and
– Kidneys

Prader-Willi syndrome
Characterized by
•Mental retardation,
•Short stature
•Hypotonia
•Profound hyperphagia
•Obesity
•Small hands and feet, and
•Hypogonadism

Angelman syndrome
• In contrast patiemts with the phenotypically distinct Angelman syndrome are born with a deletion of the same chromosomal region derived from their mothers
• Patients with Angelman syndrome are:
– Mentally retarded
– In addition they have
• Ataxic gait
• Seizures, and
• Inappropriate laughter
• Because of their laughter and ataxia, they have been referred to as “happy puppets”