<br>ZFHX3 中的外显子三核苷酸重复扩增导致脊髓小脑性共济失调 4 型：一种聚甘氨酸病,American Journal of Human Genetics

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ZFHX3 中的外显子三核苷酸重复扩增导致脊髓小脑性共济失调 4 型：一种聚甘氨酸病
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2023-11-29 , DOI: 10.1016/j.ajhg.2023.11.008
Joel Wallenius ₁ , Efthymia Kafantari ₁ , Emma Jhaveri ₁ , Sorina Gorcenco ₁ , Adam Ameur ₂ , Christin Karremo ₁ , Sigurd Dobloug ₃ , Kristina Karrman ₄ , Tom de Koning ₅ , Andreea Ilinca ₁ , Maria Landqvist Waldö ₆ , Andreas Arvidsson ₁ , Staffan Persson ₁ , Elisabet Englund ₇ , Hans Ehrencrona ₄ , Andreas Puschmann ₈

Affiliation

Neurology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, 222 42 Lund, Sweden.
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 23 Uppsala, Sweden.
Neurology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, 222 42 Lund, Sweden; Department of Neurology, Helsingborg General Hospital, 252 23 Helsingborg, Sweden.
Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 222 42 Lund, Sweden; Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office for Medical Services, Region Skåne, 221 85 Lund, Sweden.
Pediatrics, Department of Clinical Sciences Lund, Lund University, 221 84 Lund, Sweden.
Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund, Lund University, 221 84 Lund, Sweden.
Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office for Medical Services, Region Skåne, 221 85 Lund, Sweden; Pathology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, 222 42 Lund, Sweden.
Neurology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, 222 42 Lund, Sweden; SciLifeLab National Research Infrastructure, Lund University, 221 84 Lund, Sweden.

常染色体显性遗传性共济失调伴感觉神经和自主神经病变是一种高度特异性的组合表型，我们于 2014 年在两个瑞典亲属中描述了它;它的遗传原因仍然未知。在这里，我们报道了在这些家族的锌指同源盒 3 （）中发现编码聚甘氨酸的外显子 GGC 三核苷酸重复扩增。在所有受影响的家庭成员共享的基因组片段内的全基因组数据集中发现了扩展。非扩增等位基因在重复序列中携带一个或多个中断。我们还发现了另外三个科的重复扩增，它们都来自瑞典南部的斯科讷地区。重复次数扩大的个体在 15 至 60 岁时出现平衡和步态障碍，并出现感觉神经病变和扫视缓慢。在所有家系中观察到预期，并与通过两个家系成员的长读长测序确定的不同重复长度相关。受影响最严重的个体有明显的自主神经功能障碍，严重的直立性是最致残的临床特征。神经病理学显示中枢和肠道神经系统神经元中 p62 阳性胞浆内和核内包涵体，以及 α-突触核蛋白阳性。位于 16q22 位点内，脊髓小脑性共济失调 4 型（SCA4）已反复定位到该位点;我们家系的临床表型与 SCA4 中描述的独特表型吻合良好，原始 SCA4 亲属起源于瑞典。ZFHX3 在中枢和周围神经系统的神经元发育和分化中具有已知的功能。我们的研究结果表明，SCA4 是由中的重复扩增引起的。

"点击查看英文标题和摘要"

Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease

Autosomal-dominant ataxia with sensory and autonomic neuropathy is a highly specific combined phenotype that we described in two Swedish kindreds in 2014; its genetic cause had remained unknown. Here, we report the discovery of exonic GGC trinucleotide repeat expansions, encoding poly-glycine, in zinc finger homeobox 3 () in these families. The expansions were identified in whole-genome datasets within genomic segments that all affected family members shared. Non-expanded alleles carried one or more interruptions within the repeat. We also found repeat expansions in three additional families, all from the region of Skåne in southern Sweden. Individuals with expanded repeats developed balance and gait disturbances at 15 to 60 years of age and had sensory neuropathy and slow saccades. Anticipation was observed in all families and correlated with different repeat lengths determined through long-read sequencing in two family members. The most severely affected individuals had marked autonomic dysfunction, with severe orthostatism as the most disabling clinical feature. Neuropathology revealed p62-positive intracytoplasmic and intranuclear inclusions in neurons of the central and enteric nervous system, as well as alpha-synuclein positivity. is located within the 16q22 locus, to which spinocerebellar ataxia type 4 (SCA4) repeatedly had been mapped; the clinical phenotype in our families corresponded well with the unique phenotype described in SCA4, and the original SCA4 kindred originated from Sweden. ZFHX3 has known functions in neuronal development and differentiation n both the central and peripheral nervous system. Our findings demonstrate that SCA4 is caused by repeat expansions in .

更新日期：2023-11-29

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