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Previously described sequence variant in CDK5RAP2 gene in a Pakistani family with autosomal recessive primary
Muhammad Jawad Hassan1, Maryam Khurshid, Zahid Azeem
1Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan. mjhassan@bs.qau.edu.pk
Background:
Autosomal Recessive Primary Microcephaly (MCPH) is a disorder of neurogenic mitosis. MCPH leads to reduced cerebral cortical volume and hence, reduced head circumference associated with mental retardation of variable degree. Genetic heterogeneity is well documented in patients with MCPH with six loci known, while pathogenic sequence variants in four respective genes have been identified so far. Mutations in CDK5RAP2 gene at MCPH3 locus have been least involved in causing MCPH phenotype.
Methods:
All coding exons and exon/intron splice junctions of CDK5RAP2 gene were sequenced in affected and normal individuals of Pakistani MCPH family of Kashmiri origin, which showed linkage to MCPH3 locus on chromosome 9q33.2.
Results:
A previously described nonsense mutation [243 T>A (S81X)] in exon 4 of CDK5RAP2 gene has been identified in the Pakistani family, presented here, with MCPH Phenotype. Genomic and cDNA sequence comparison revealed that the exact nomenclature for this mutation is 246 T>A (Y82X).
Conclusion:
Recurrent observation of Y82X mutation in CDK5RAP2 gene in this Pakistani family may be a sign of confinement of a rare ancestral haplotype carrying this pathogenic variant within Northern Pakistani population, as this has not been reported in any other population.
Insights
A specific mutation in the CDK5RAP2 gene, Y82X, causes Primary Microcephaly (MCPH) in a Pakistani family. This finding suggests a rare ancestral haplotype may be present in this population.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Autosomal Recessive Primary Microcephaly (MCPH) is a neurodevelopmental disorder characterized by reduced brain size and intellectual disability.
- MCPH exhibits genetic heterogeneity, with several causative genes identified, though mutations in CDK5RAP2 are less common.
- The CDK5RAP2 gene is implicated in cell division and brain development.
Purpose of the Study:
- To investigate the genetic basis of MCPH in a Pakistani family of Kashmiri origin.
- To identify the specific mutation in the CDK5RAP2 gene responsible for the MCPH phenotype in this family.
Main Methods:
- Genetic linkage analysis was performed to map the MCPH locus to chromosome 9q33.2.
- Sequencing of all coding exons and splice junctions of the CDK5RAP2 gene was conducted in affected and unaffected family members.
Main Results:
- A nonsense mutation, previously reported as S81X but confirmed as Y82X (246 T>A) in exon 4 of the CDK5RAP2 gene, was identified in the affected family members.
- This mutation was found to segregate with the MCPH phenotype within the family.
Conclusions:
- The recurrent identification of the Y82X mutation in this Pakistani family suggests it may be linked to a rare ancestral haplotype specific to the Northern Pakistani population.
- This finding expands the known spectrum of CDK5RAP2 mutations associated with MCPH and highlights potential founder effects in specific ethnic groups.
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