Brewer Megan, Changi Febriani, Antonellis Anthony, Fischbeck Kurt, Polly Patsie, Nicholson Garth, Kennerson Marina
Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia.
Neurogenetics. 2008 Jul;9(3):191-5. doi: 10.1007/s10048-008-0126-4. Epub 2008 May 6.
X-linked Charcot-Marie-Tooth (CMTX) disease is a common inherited degenerative disorder of the peripheral nerve. Previously, our laboratory identified a large New Zealand/United Kingdom (NZ/UK) family mapping to the CMTX3 locus (Xq26.3-27.1). We have now identified a second large, Australian X-linked CMT family that links to the CMTX3 locus. This new family has the same phenotype as our previously described CMTX3 family, with slightly milder disease in males than CMTX1 and asymptomatic carrier females. This study also includes the re-analysis of one of the original US pedigrees reporting the CMTX3 locus. The large Australian family shared the complete disease haplotype with our original NZ/UK family, while the American family shared only the distal portion of the disease haplotype. Comparison of the frequency of the CMTX3 haplotype to the normal population showed strong statistical evidence (p < 0.0001) indicating that the smaller shared haplotype is identical by descent. This suggests that the new CMTX3 family, our previously reported family, and the original American CMTX3 family have a common ancestor, and the disease in these families is caused by a founder mutation. The ancestral recombination observed in the American family refines the CMTX3 interval to a 2.5 Mb region between DXS984 and DXS8106. In this region, 11 out of the 15 annotated genes have been excluded for pathogenic mutations.
X连锁型夏科-马里-图斯（CMTX）病是一种常见的遗传性周围神经退行性疾病。此前，我们实验室鉴定出一个映射到CMTX3基因座（Xq26.3 - 27.1）的大型新西兰/英国（NZ/UK）家系。我们现在又鉴定出第二个与CMTX3基因座连锁的大型澳大利亚X连锁型CMT家系。这个新家系与我们之前描述的CMTX3家系具有相同的表型，男性患者的病情比CMTX1稍轻，女性携带者无症状。本研究还包括对最初报道CMTX3基因座的一个美国家系进行重新分析。这个大型澳大利亚家系与我们最初的NZ/UK家系共享完整的致病单倍型，而美国家系仅共享致病单倍型的远端部分。将CMTX3单倍型在正常人群中的频率进行比较，结果显示出强有力的统计学证据（p < 0.0001），表明较小的共享单倍型是同源的。这表明新的CMTX3家系、我们之前报道的家系以及最初的美国CMTX3家系有一个共同的祖先，这些家系中的疾病是由一个奠基者突变引起的。在美国家系中观察到的祖先重组将CMTX3区间缩小到DXS984和DXS8106之间的一个2.5 Mb区域。在这个区域中，15个注释基因中有11个已被排除存在致病突变。
