Hassan Muhammad Jawad, Khurshid Maryam, Azeem Zahid, John Peter, Ali Ghazanfar, Chishti Muhammad Salman, Ahmad Wasim
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
BMC Med Genet. 2007 Sep 1;8:58. doi: 10.1186/1471-2350-8-58.
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.
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.
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).
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.
常染色体隐性原发性小头畸形（MCPH）是一种神经原性有丝分裂障碍疾病。MCPH会导致大脑皮质体积减小，进而导致头围减小，并伴有不同程度的智力发育迟缓。MCPH患者中遗传异质性已有充分记录，已知有六个基因座，目前已在四个相应基因中鉴定出致病序列变异。位于MCPH3基因座的CDK5RAP2基因突变最少参与导致MCPH表型。
对克什米尔血统的巴基斯坦MCPH家族的患病个体和正常个体的CDK5RAP2基因的所有编码外显子和外显子/内含子剪接连接进行测序，该家族显示与9号染色体q33.2上的MCPH3基因座连锁。
在本文报道的患有MCPH表型的巴基斯坦家族中，已在CDK5RAP2基因第4外显子中鉴定出先前描述的无义突变[243 T>A（S81X）]。基因组和cDNA序列比较显示，该突变的确切命名为246 T>A（Y82X）。
在这个巴基斯坦家族中反复观察到CDK5RAP2基因中的Y82X突变，可能表明在巴基斯坦北部人群中存在一种携带这种致病变异的罕见祖先单倍型，因为在其他人群中尚未有此报道。
