Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype.
Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype.
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DOI：
10.1002/ajmg.b.32332
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Margolis R
中科院分区：
文献类型：
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作者：
Krause A;Mitchell C;Essop F;Tager S;Temlett J;Stevanin G;Ross C;Rudnicki D;Margolis R
亨廷顿病 (HD) 是一种进行性常染色体显性神经退行性疾病，其特征是运动异常、认知能力下降和精神症状，由 4p 染色体上亨廷顿 (HTT) 基因的 CAG 重复扩增引起。染色体 16q24.2 上的 junctophilin-3 (JPH3) 基因中的 CAG/CTG 重复扩增会导致亨廷顿病样表型 (HDL2)。迄今为止，所有 HDL2 患者都有一定的非洲血统。本研究旨在描述南非人亨廷顿病表型的遗传基础，并调查 JPH3 突变的可能起源。在转诊进行 HD 诊断检测的无关南非个体样本中，62% (106/171) 的白人患者的 HTT 有所扩大，而黑人患者中只有 36% (47/130) 的 HTT 有所扩大。然而，15% (20/130) 的南非黑人患者和没有白人患者 (0/171) 出现 JPH3 扩增，证实了亨廷顿病样 2 (HDL2) 的诊断。 HDL2 患者与 HD 患者有许多共同的临床特征，并且在许多情况下在临床上无法区分，尽管 HDL2 患者的平均发病和诊断年龄比 HD 晚 5 年，并且个体临床特征可能更突出。 HDL2 突变对具有非洲血统的南非人的 HD 表型有显着影响。对主要来自南非和北美的 31 个家庭进行的 JPH3 单倍型研究提供了创始人突变的证据，并支持所有 HDL2 患者的共同非洲起源。对具有 HD 表型和非洲血统的个体进行分子检测应包括常规检测 JPH3 突变。
Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations.