Abstract
BackgroundAutosomal 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.MethodsAll 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.ResultsA 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).ConclusionRecurrent 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.
Highlights
Autosomal Recessive Primary Microcephaly (MCPH) is a disorder of neurogenic mitosis
MCPH is genetically heterogeneous with six loci (MCPH1–MCPH6) mapped to date [3,4,5,6,7,8] while four of the corresponding genes [Microcephalin (MIM-607117) at MCPH1, CDK5RAP2 (MIM-608201) at MCPH3, ASPM (MIM-605481) at MCPH5 and CENPJ (MIM-609279) at MCPH6] have been identified [9,10,11]
The MCPH5 is most prevalent in patients with primary microcephaly world wide and at least 30 pathogenic sequence variants in the corresponding gene ASPM are known to date without any significant correlation between position of mutation and severity of microcephaly [12,13,14,15,16]
Summary
Autosomal Recessive Primary Microcephaly (MCPH) is a disorder of neurogenic mitosis. MCPH leads to reduced cerebral cortical volume and reduced head circumference associated with mental retardation of variable degree. Autosomal recessive primary microcephaly (MCPH), a rare neurodevelopmental disorder, is characterized by reduced head circumference of at least 4 standard deviations below the age- and sex- related population specific means; associated with non progressive mental retardation of variable degree but no other neurological deficit. The MCPH5 is most prevalent in patients with primary microcephaly world wide and at least 30 pathogenic sequence variants in the corresponding gene ASPM (abnormal spindle like microcephaly associated) are known to date without any significant correlation between position of mutation and severity of microcephaly [12,13,14,15,16]. Three mutations in the CENPJ (centromere associated protein J) gene at MCPH6 locus are known in Brazilian and Pakistani families with autosomal recessive primary microcephaly [11,24]. A role for CENPJ in centrosome duplication at the beginning of mitosis has been proposed [26]
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