Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).
Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).
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DOI：
10.1007/s00439-018-1929-5
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发表时间：
2018-09
期刊：
影响因子：
5.3
通讯作者：
Wieczorek D
中科院分区：
文献类型：
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作者：
Bramswig NC;Bertoli-Avella AM;Albrecht B;Al Aqeel AI;Alhashem A;Al-Sannaa N;Bah M;Bröhl K;Depienne C;Dorison N;Doummar D;Ehmke N;Elbendary HM;Gorokhova S;Héron D;Horn D;James K;Keren B;Kuechler A;Ismail S;Issa MY;Marey I;Mayer M;McEvoy-Venneri J;Megarbane A;Mignot C;Mohamed S;Nava C;Philip N;Ravix C;Rolfs A;Sadek AA;Segebrecht L;Stanley V;Trautman C;Valence S;Villard L;Wieland T;Engels H;Strom TM;Zaki MS;Gleeson JG;Lüdecke HJ;Bauer P;Wieczorek D
NALCN是一种保守的阳离子通道，传导永久性钠漏电流，调节静息膜电位和神经元兴奋性。它是大型离子通道复合物“NALCN通道体”的一部分，由包括UNC 80和UNC 79在内的多种蛋白质组成。主要的神经元表达模式及其功能表明在神经元功能和疾病中的重要作用。到目前为止，双等位基因NALCN和UNC 80变体已在少数个体中描述，分别导致婴儿张力减退、精神发育迟滞和特征性面容1（IHPRF 1，OMIM 615419）和2（IHPRF 2，OMIM 616801）。S5/S6成孔节段中的杂合从头NALCN错义变体导致肢体和面部先天性挛缩、肌张力减退和发育迟缓（CLIFAHDD，OMIM 616266），并伴有一些临床重叠。在这项研究中，我们提出了16个新的个人与双等位基因NALCN变异，1个人与杂合子从头NALCN错义变异和一个有趣的临床表型没有挛缩，和12个人与双等位基因UNC 80变异的详细临床信息。我们首次报告了位于预测的S6孔形成单位中的错义NALCN变体，该变体以常染色体隐性方式遗传，导致轻度IHPRF 1。我们显示了临床变异的证据，特别是在IHPRF 1受影响的个体中，并讨论了IHPRF 1和IHPRF 2表型之间的差异。总之，我们提供了一个全面的概述IHPRF 1和IHPRF 2表型的基础上最大的队列的个人报告，迄今为止，并提供更多的见解，这些神经发育疾病的临床表型，以帮助改善受影响的家庭咨询。
NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the “NALCN channelosome”, consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1-and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.
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影响因子：
64.8
作者：
Lin, Yingxi;Bloodgood, Brenda L.;Hauser, Jessica L.;Lapan, Ariya D.;Koon, Alex C.;Kim, Tae-Kyung;Hu, Linda S.;Malik, Athar N.;Greenberg, Michael E.
通讯作者：
Greenberg, Michael E.
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
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影响因子：
1.9
作者：
Gal, Moran;Magen, Daniella;Mandel, Hanna
通讯作者：
Mandel, Hanna
影响因子：
5.3
作者：
Bramswig, Nuria C.;Luedecke, Hermann-Josef;Wieczorek, Dagmar
通讯作者：
Wieczorek, Dagmar
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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