PDF(Pubmed)
Abstract：
Recessive loss-of-function variations in HINT1 cause a peculiar subtype of Charcot-Marie-Tooth disease: neuromyotonia and axonal neuropathy (NMAN; OMIM[#137200]). With 25 causal variants identified worldwide, HINT1 mutations are among the most common causes of recessive neuropathy. The majority of patients are compound heterozygous or homozygous for a Slavic founder variant (c.110G>C, p.Arg37Pro) that has spread throughout Eurasia and America.
In a cohort of 46 genetically unresolved Lithuanian patients with suspected inherited neuropathy, we identified eight families with HINT1 biallelic variations. Most patients displayed sensorimotor or motor-predominant axonal polyneuropathy and were homozygous for the p.Arg37Pro variant. However, in three families we identified a novel variant (c.299A>G, p.Glu100Gly). The same variant was also found in an American patient with distal hereditary motor neuropathy in compound heterozygous state (p.Arg37Pro/p.Glu100Gly). Haplotype analysis demonstrated a shared chromosomal region of 1.9 Mb between all p.Glu100Gly carriers, suggesting a founder effect. Functional characterization showed that the p.Glu100Gly variant renders a catalytically active enzyme, yet highly unstable in patient cells, thus supporting a loss-of-function mechanism.
Our findings broaden NMAN\'s genetic epidemiology and have implications for the molecular diagnostics of inherited neuropathies in the Baltic region and beyond. Moreover, we provide mechanistic insights allowing patient stratification for future treatment strategies.
In a cohort of 46 genetically unresolved Lithuanian patients with suspected inherited neuropathy, we identified eight families with HINT1 biallelic variations. Most patients displayed sensorimotor or motor-predominant axonal polyneuropathy and were homozygous for the p.Arg37Pro variant. However, in three families we identified a novel variant (c.299A>G, p.Glu100Gly). The same variant was also found in an American patient with distal hereditary motor neuropathy in compound heterozygous state (p.Arg37Pro/p.Glu100Gly). Haplotype analysis demonstrated a shared chromosomal region of 1.9 Mb between all p.Glu100Gly carriers, suggesting a founder effect. Functional characterization showed that the p.Glu100Gly variant renders a catalytically active enzyme, yet highly unstable in patient cells, thus supporting a loss-of-function mechanism.
Our findings broaden NMAN\'s genetic epidemiology and have implications for the molecular diagnostics of inherited neuropathies in the Baltic region and beyond. Moreover, we provide mechanistic insights allowing patient stratification for future treatment strategies.
摘要：
HINT1中的隐性功能丧失变异引起Charcot-Marie-Tooth病的一种特殊亚型:神经肌强直和轴索神经病(NMAN;OMIM[#137200])。在全球范围内确定了25个因果变异，HINT1突变是隐性神经病的最常见原因之一。大多数患者是斯拉夫创始人变体的复合杂合或纯合（c.110G>C，p.Arg37Pro）已遍及欧亚大陆和美洲。
在46名疑似遗传性神经病的遗传未解决的立陶宛患者中，我们确定了八个具有HINT1双等位基因变异的家族。大多数患者表现为感觉运动或运动型轴索多发性神经病，并且是p.Arg37Pro变体的纯合子。然而,在三个家族中，我们确定了一个新的变体(c.299A>G，p.Glu100Gly）。在复合杂合状态的远端遗传性运动神经病的美国患者中也发现了相同的变体（p。Arg37Pro/p。Glu100Gly）。单倍型分析表明，所有p.Glu100Gly携带者之间共享1.9Mb的染色体区域，暗示了创始人的影响。功能表征表明，p.Glu100Gly变体提供催化活性酶，然而在患者细胞中高度不稳定，从而支持功能丧失机制。
我们的发现拓宽了NMAN的遗传流行病学，并对波罗的海及其他地区遗传性神经病的分子诊断具有重要意义。此外，我们提供了机械性的见解,使患者能够对未来的治疗策略进行分层.
在46名疑似遗传性神经病的遗传未解决的立陶宛患者中，我们确定了八个具有HINT1双等位基因变异的家族。大多数患者表现为感觉运动或运动型轴索多发性神经病，并且是p.Arg37Pro变体的纯合子。然而,在三个家族中，我们确定了一个新的变体(c.299A>G，p.Glu100Gly）。在复合杂合状态的远端遗传性运动神经病的美国患者中也发现了相同的变体（p。Arg37Pro/p。Glu100Gly）。单倍型分析表明，所有p.Glu100Gly携带者之间共享1.9Mb的染色体区域，暗示了创始人的影响。功能表征表明，p.Glu100Gly变体提供催化活性酶，然而在患者细胞中高度不稳定，从而支持功能丧失机制。
我们的发现拓宽了NMAN的遗传流行病学，并对波罗的海及其他地区遗传性神经病的分子诊断具有重要意义。此外，我们提供了机械性的见解,使患者能够对未来的治疗策略进行分层.
