Allelic and phenotypic heterogeneity in Junctophillin-3 related neurodevelopmental and movement disorders.
Allelic and phenotypic heterogeneity in Junctophillin-3 related neurodevelopmental and movement disorders.
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DOI：
10.1038/s41431-021-00866-1
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Houlden H
中科院分区：
文献类型：
--
作者：
Bourinaris T;Athanasiou A;Efthymiou S;Wiethoff S;Salpietro V;Houlden H
嗜连接蛋白-3属于一种三蛋白连接复合物，参与神经元兴奋性的调节，并参与电压门控离子通道和内质网（ryanodine）网状受体之间连接膜结构的形成。位于junctophilin-3基因（JPH 3）内的单等位基因三核苷酸重复扩增与临床上类似于亨廷顿病（HD）的罕见常染色体显性（AD）迟发性（和进行性）疾病有关，称为HD样2（HDL 2; MIM# 606438）。尽管HDL 2的确切分子机制尚未完全阐明，但异常转录物（含有三核苷酸重复序列）的毒性功能获得和（全长）junctophilin-3表达丧失均与HDL 2病理生理学有关。在这项研究中，我们通过全外显子组测序（WES）鉴定了JPH 3纯合截短变体[NM_020655.4：c.17405dup; p.（Val581Argfs*137）]。在患有遗传学上未确定的神经发育异常（包括运动里程碑延迟、社会交流异常、语言困难和边缘性认知障碍）和自婴儿早期起的肌张力障碍的阵发性发作的女性个体中。我们的研究扩展了JPH 3相关的突变谱和临床表型，暗示了异质性神经发育表型和早发性阵发性运动障碍中Junctophilin-3的丢失。
Junctophilin-3 belongs to a triprotein junctional complex implicated in the regulation of neuronal excitability and involved in the formation of junctional membrane structures between voltage-gated ion channels and endoplasmic (ryanodine) reticular receptors. A monoallelic trinucleotide repeat expansion located within the junctophilin-3 gene (JPH3) has been implicated in a rare autosomal dominant (AD) late-onset (and progressive) disorder clinically resembling Huntington disease (HD), and known as HD-like 2 (HDL2; MIM# 606438). Although the exact molecular mechanisms underlying HDL2 has not yet been fully elucidated, toxic gain-of-function of the aberrant transcript (containing the trinucleotide repeat) and loss of expression of (full-length) junctophilin-3 have both been implicated in HDL2 pathophysiology. In this study, we identified by whole exome sequencing (WES) a JPH3 homozygous truncating variant [NM_020655.4: c.17405dup; p.(Val581Argfs*137)]. in a female individual affected with genetically undetermined neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. Our study expands the JPH3-associated mutational spectrum and clinical phenotypes, implicating the loss of Junctophilin-3 in heterogeneous neurodevelopmental phenotypes and early-onset paroxysmal movement disorders.
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DOI：
10.1002/ajmg.b.32332
发表时间：
2015-10
期刊：
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
影响因子：
--
作者：
Krause A;Mitchell C;Essop F;Tager S;Temlett J;Stevanin G;Ross C;Rudnicki D;Margolis R
通讯作者：
Margolis R
影响因子：
9.8
作者：
Salpietro, Vincenzo;Malintan, Nancy T.;Houlden, Henry
通讯作者：
Houlden, Henry
影响因子：
9.8
作者：
Mencacci, Niccolo E.;Kamsteeg, Erik-Jan;Bhatia, Kailash P.
通讯作者：
Bhatia, Kailash P.
影响因子：
4.6
作者：
Garbino, Alejandro;van Oort, Ralph J.;Wehrens, Xander H. T.
通讯作者：
Wehrens, Xander H. T.
影响因子：
11.2
作者：
Rudnicki, Dobrila D.;Holmes, Susan E.;Margolis, Russell L.
通讯作者：
Margolis, Russell L.