Which of the following polymorphism has been linked to performance on working memory tasks in patients with schizophrenia?
B. COMT polymorphism has been widely studied in schizophrenia. COMT stands for catechol-o-methyl transferase. It is an important enzyme in the breakdown of dopamine in prefrontal area of the brain. Though monoamine oxidase is the major enzyme in dopamine metabolism in most other brain regions, COMT assumes special significance in the prefrontal brain area, at least in primates; the dopamine (reuptake) transporter is present at a low density in the prefrontal area compared to the striatum. The gene for COMT is located on chromosome 22q11. The deletion of 22q11 results in velo cardio facial syndrome (VCFS) or di George syndrome. As many as 30% of affected individuals with VCFS meet diagnostic criteria for schizophrenia. The existence of a valine-to-methionine (Val/Met) polymorphism has been noted, stimulating more interest in COMT. Val/Val genotype results in a higher activity form, while Met/ Met is associated with lower activity of the enzyme. The higher activity variant leads to faster breakdown and reduced availability of prefrontal dopamine. This may be associated with poorer working memory function or inefficient prefrontal activity in such tasks.
Findings implicating GABA in working memory have been reported. Decreased expression of the GABA biosynthetic enzyme glutamic acid decarboxylase 67 (GAD67), encoded by GAD1, is found in the post-mortem brain tissue of schizophrenia patients. It has been shown that the variation in GAD1 influences multiple domains of cognition, including declarative memory, attention, and working memory. There may be epistasis between SNPs in COMT and GAD1, suggesting a potential biological synergism, leading to increased risk. These coincident results implicate GAD1 in the aetiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity in addition to COMT changes (Straub et al. 2007).
References:
Which one of the following processes can inactivate a gene?
A. Chemical modification of DNA is one method by which gene expression is controlled. This can be achieved by adding methyl groups to some of the amino acids in DNA. In females, randomly picked X chromosomes undergo methylation (Lyon’s hypothesis) resulting in Barr bodies. In fragile-X syndrome, the fragile X site undergoes methylation, resulting in reduced expression of the FMR1 gene on X chromosomes. This produces the phenotype of fragile-X syndrome. Unwinding of DNA is an important step that precedes DNA synthesis (replication from the template). Crossing over, condensation, and uncoiling are seen in the normal cell cycle. Genes do not become inactivated during such processes and subsequent cellular synthetic processes are intact.
Reference:
Expression of genes depending upon the parent of origin is a phenomenon seen in:
A. In genomic imprinting, the disease phenotype expressed depends on whether the allele is of maternal or paternal lineage. This parent-of-origin phenomenon is an important exception to Mendelian inheritance patterns. An often-quoted example is Angelman’s syndrome and Prader–Willi syndrome. These are two clinically distinct, genetic diseases associated with genomic imprinting on chromosome 15q11-q13. Major diagnostic criteria for Prader–Willi syndrome include mental retardation, hypotonia, hyperphagia and obesity, hypogonadism, and maturational delay. In Angelman’s syndrome ataxia, tremors, seizures, hyperactivity, and profound mental retardation are accompanied by outbreaks of laughter (gelastic attacks). Approximately 70% of patients with Prader–Willi syndrome have a deletion in their paternally derived 15q11- q13. Maternal uniparental disomy (inheriting both copies from the mother when the embryo is formed) occurs in most of the remaining patients (25%). Most patients with Angelman’s syndrome have a deletion in their maternally derived 15q11-q13. Paternal uniparental disomy occurs in about 4% of Angelman’s syndrome. This parent-of-origin effect is thought to be due to DNA methylation defects.
Genetic anticipation refers to the phenomenon wherein phenotypic expression of a mutation occurs earlier in successive generations. This is seen in Huntington’s disease and other trinucleotide repeat diseases. Autosomal aneuploidy, such as Down’s syndrome, are not ‘inherited’ diseases but show a correlation with maternal age, as an ageing ovum is prone to more cell division errors. This is not the same as the parent-of-origin effect.
Which of the following clinical scenarios is most likely to be a result of genetic anticipation?
C. The anticipation phenomenon refers to an aspect of several genetic disorders in which the age at onset decreases and the severity of illness increases in successive generations. The classical example is Huntington’s disease. This is also noted in other trinucleotide repeat syndromes. Trinucleotide repeats undergo expansion during germ cell division, which further destabilizes the mutant trinucleotide loci and the probability of the phenotypic expression thus increases with every gametogenesis. This occurs more frequently with oogenesis than spermatogenesis, leading to pronounced anticipation in maternally transmitted trinucleotide diseases. Carriers of a heterozygous recessive mutation may show cellular level abnormalities lifelong without overt disease manifestation; this is not genetic anticipation.
A large pedigree is observed for the occurrence of a rare form of recurrent strokes. All affected females in the pedigree produce affected children of both sexes. But none of the affected males pass the disease on to the next generation.
The most likely mode of inheritance is:
C. This description refers to MELAS, which shows mitochondrial inheritance. In mitochondrial inheritance, the disease is transmitted from females to males but not from males to females. MELAS stands for mitochondrial myopathy, encephalopathy, lactic acidosis, and recurrent stroke. MELAS is a progressive neurodegenerative disorder. Patients may present with seizures, diabetes mellitus, hearing loss, short stature, and exercise intolerance.
Click to expand