The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4
The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4
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DOI：
10.1111/j.1399-0004.2007.00774.x
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发表时间：
2007-04-01
影响因子：
3.5
通讯作者：
Espinos, C.
中科院分区：
文献类型：
--
作者：
Claramunt, R.;Sevilla, T.;Espinos, C.
腓骨肌萎缩症（CMT）4型（CMT 4）是常染色体隐性遗传性运动和感觉神经病（HMSN）的名称。当我们开始这项研究时，已经在欧洲吉普赛人群中确定了与遗传性周围神经病相关的三个基因或位点：HMSN-Lom（MIM 601455），HMSN-Russe（MIM 605285）和先天性白内障面部畸形神经病综合征（MIM 604168）。我们已经进行了一系列的20个西班牙吉普赛家庭诊断与脱髓鞘CMT疾病兼容的常染色体隐性遗传性状的遗传分析。我们发现N-myc下游调节基因1基因中的p.R148X突变与4个家庭的HMSN-Lom有关，也可能与另外3个家庭的HMSN-Russe基因座相关。我们还研究了CMT 4C基因座，因为临床相似性，并表明在10个家庭中，该疾病是由位于SH 3结构域和tetratricopeptide repeats 2（SH 3 TC 2）基因上的突变引起的：21条染色体中的20条中的p.R1109X和仅一条染色体中的p.C737_P738delinsX。此外，SH 3 TC 2 p.R1109X突变与保守的单倍型相关，因此，可能是吉普赛人的私人创始人突变。对等位基因年龄的估计显示，SH 3 TC 2 p.R1109X突变可能出现在大约225年前，可能是瓶颈的结果。
Charcot-Marie-Tooth (CMT) disease type 4 (CMT4) is the name given to autosomal recessive forms of hereditary motor and sensory neuropathy (HMSN). When we began this study, three genes or loci associated with inherited peripheral neuropathies had already been identified in the European Gypsy population: HMSN-Lom (MIM 601455), HMSN-Russe (MIM 605285) and the congenital cataracts facial dysmorphism neuropathy syndrome (MIM 604168). We have carried out genetic analyses in a series of 20 Spanish Gypsy families diagnosed with a demyelinating CMT disease compatible with an autosomal recessive trait. We found the p.R148X mutation in the N-myc downstream-regulated gene 1 gene to be responsible for the HMSN-Lom in four families and also possible linkage to the HMSN-Russe locus in three others. We have also studied the CMT4C locus because of the clinical similarities and showed that in 10 families, the disease is caused by mutations located on the SH3 domain and tetratricopeptide repeats 2 (SH3TC2) gene: p.R1109X in 20 out of 21 chromosomes and p.C737_P738delinsX in only one chromosome. Moreover, the SH3TC2 p.R1109X mutation is associated with a conserved haplotype and, therefore, may be a private founder mutation for the Gypsy population. Estimation of the allelic age revealed that the SH3TC2 p.R1109X mutation may have arisen about 225 years ago, probably as the consequence of a bottleneck.