Ghani-Kakhki M, Robinson P N, Morlot S, Mitter D, Trimborn M, Albrecht B, Varon R, Sperling K, Neitzel H
Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Mol Syndromol. 2012 Jun;3(1):6-13. doi: 10.1159/000338975. Epub 2012 Jun 13.
Primary microcephaly MCPH1 is an extremely rare autosomal recessive disorder associated with congenital microcephaly, mental retardation and a distinctive cellular phenotype of misregulated chromosome condensation. The MCPH1 gene encodes an 835-amino acid protein, microcephalin, which contains 1 N-terminal and 2 C-terminal BRCT (BRCA1 C-terminus) domains. BRCT domains are predominantly found in proteins involved in cell cycle control and DNA repair. Here we describe 1 novel and 1 previously reported MCPH1 missense mutation, p.Trp75Arg and p.Ser72Leu, respectively, in the N-terminal BRCT domain of microcephalin associated with severe congenital microcephaly. Both residues are entirely conserved in the MCPH1 orthologs of all vertebrate species and Drosophila. Proliferating lymphocytes of the patients with p.Trp75Arg and p.Ser72Leu show the unique cellular MCPH1 phenotype of misregulated chromosome condensation, indicating that these missense alterations disrupt the function of the N-terminal BRCT domain of the protein. Interestingly, both residues are strictly conserved in BRCT domains of BRCA1. ClustalW alignments show that the residue p.Ser72 of microcephalin corresponds to p.Ser1715 of the N-terminal BRCT domain of BRCA1, while the microcephalin residue p.Trp75 is analogous to p.Trp1718 in the N-terminal BRCT and to p.Trp1837 in C-terminal BRCT domains of BRCA1. Missense alterations for all 3 corresponding BRCA1 residues were described and are predicted to be deleterious resulting in the destabilization of the BRCA1 protein. Our data on the 2 MCPH1 missense alterations provide further evidence for the functional significance of these residues in BRCT domains.
原发性小头畸形MCPH1是一种极其罕见的常染色体隐性疾病，与先天性小头畸形、智力发育迟缓以及染色体凝聚调控异常的独特细胞表型相关。MCPH1基因编码一种含835个氨基酸的蛋白质——小头畸形蛋白，该蛋白含有1个N端和2个C端BRCT（BRCA1 C末端）结构域。BRCT结构域主要存在于参与细胞周期调控和DNA修复的蛋白质中。在此，我们描述了与严重先天性小头畸形相关的小头畸形蛋白N端BRCT结构域中分别为1个新的和1个先前报道过的MCPH1错义突变，即p.Trp75Arg和p.Ser72Leu。这两个残基在所有脊椎动物物种和果蝇的MCPH1直系同源物中完全保守。携带p.Trp75Arg和p.Ser72Leu的患者的增殖淋巴细胞表现出染色体凝聚调控异常的独特细胞MCPH1表型，表明这些错义改变破坏了该蛋白N端BRCT结构域的功能。有趣的是，这两个残基在BRCA1的BRCT结构域中严格保守。ClustalW比对显示，小头畸形蛋白的p.Ser72残基对应于BRCA1 N端BRCT结构域的p.Ser1715，而小头畸形蛋白的p.Trp75残基类似于BRCA1 N端BRCT结构域中的p.Trp1718以及C端BRCT结构域中的p.Trp1837。已描述了所有3个相应BRCA1残基的错义改变，预计这些改变具有有害性，会导致BRCA1蛋白不稳定。我们关于这2个MCPH1错义改变的数据为这些残基在BRCT结构域中的功能重要性提供了进一步证据。
