The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND

被引：0

作者：

Qebibo, Leila ^{[1
,2
,3
]}

Davakan, Amael ^{[4
,5
]}

Nesson-Dauphin, Mathilde ^{[3
]}

Boulali, Najlae ^{[4
,5
]}

Siquier-Pernet, Karine ^{[3
]}

Afenjar, Alexandra ^{[2
]}

Amiel, Jeanne ^{[6
]}

Bartholdi, Deborah ^{[7
]}

Barth, Magalie ^{[8
]}

Blondiaux, Eleonore ^{[9
]}

Cristian, Ingrid ^{[10
]}

Frazier, Zoe ^{[11
]}

Goldenberg, Alice ^{[12
,13
]}

Good, Jean-Marc ^{[14
,15
]}

Salussolia, Catherine Lourdes ^{[11
]}

Sahin, Mustafa ^{[11
]}

McCullagh, Helen ^{[16
]}

McDonald, Kimberly ^{[17
]}

McRae, Anne ^{[18
,19
,20
]}

Morrison, Jennifer ^{[10
]}

Pinner, Jason

Shinawi, Marwan ^{[21
]}

Toutain, Annick ^{[22
]}

Vyhnalkova, Emilie ^{[23
]}

Wheeler, Patricia G. ^{[10
]}

Wilnai, Yael ^{[24
]}

Hausman-Kedem, Moran ^{[25
,26
]}

Coolen, Marion ^{[3
]}

Cantagrel, Vincent ^{[3
]}

Burglen, Lydie ^{[1
,2
,3
]}

Lory, Philippe ^{[4
,5
]}

机构：

[1] Sorbonne Univ, Armand Trousseau Hosp, AP HP, Pediat Neurogenet Lab,Dept Genet, Paris, France

[2] Sorbonne Univ, Armand Trousseau Hosp, AP HP, Reference Ctr Cerebellar Malformat & Congenital Di, Paris, France

[3] Univ Paris Cite, Imagine Inst, INSERM, Dev Brain Disorders Lab,UMR1163, Paris, France

[4] Univ Montpellier, IGF, CNRS, INSERM, Montpellier, France

[5] LabEx Ion Channel Sci & Therapeut, Montpellier, France

[6] Necker Enfants Malad Univ Hosp, APHP, Serv Med Genom Malad Rares, Paris, France

[7] Univ Bern, Bern Univ Hosp, Dept Human Genet, Inselspital, Bern, Switzerland

[8] Angers Univ Hosp, Dept Biochem & Genet, Angers, France

[9] Sorbonne Univ, Armand Trousseau Hosp, APHP, Dept Radiol, Paris, France

[10] Orlando Hlth, Arnold Palmer Hosp Children, Orlando, FL USA

[11] Harvard Med Sch, Dept Neurol, Boston Childrens Hosp, Rosamund Stone Zander Translat Neurosci Ctr, Boston, MA USA

[12] Univ Rouen Normandie, CHU Rouen, INSERM, Dept Genet,U1245, Rouen, France

[13] Univ Rouen Normandie, Reference Ctr Dev Disorders, Rouen, France

[14] Lausanne Univ Hosp CHUV, Div Genet Med, Lausanne, Switzerland

[15] Univ Lausanne, Lausanne, Switzerland

[16] Leeds Teaching Hosp NHS Trust, Leeds, England

[17] Univ Louisville, Norton Childrens Hosp, Dept Pediat, Louisville, KY USA

[18] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL USA

[19] Sydney Childrens Hosp Network, Ctr Clin Genet, Sydney, Australia

[20] Univ New South Wales, Sydney, Australia

[21] Washington Univ, Sch Med, Dept Pediat, Div Genet & Genom Med, St Louis, MO USA

[22] Ctr Hosp Univ, Unite Fonct Genet Med, Tours, France

[23] Charles Univ Prague, Motol Univ Hosp, Prague, Czech Republic

[24] Tel Aviv Sourasky Med Ctr, Genet Inst, Tel Aviv, Israel

[25] Tel Aviv Med Ctr & Sch Med, Dana Dwek Childrens Hosp, Pediat Neurol Inst, Tel Aviv, Israel

[26] Tel Aviv Univ, Fac Med & Hlth Sci, Tel Aviv, Israel

来源：

GENETICS IN MEDICINE | 2025年 / 27卷 / 03期

关键词：

CACNA1G gene; Cerebellum; Neurodevelopment; Spinocerebellar ataxia; T-type voltage-gated calcium; channel; MUTATIONS;

D O I：

10.1016/j.gim.2024.101337

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Purpose: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. Methods: We describe 19 patients with congenital CACNA1G-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. Results: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. Conclusion: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia. (c) 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

引用

页数：17

共 1 条

[1] Profiling the array of Cav3.1 variants from the human T-type calcium channel gene CACNA1G:: Alternative structures, developmental expression, and biophysical variations
Emerick, Mark C.
Stein, Rebecca
Kunze, Robin
McNulty, Megan M.
Regan, Melissa R.
Hanck, Dorothy A.
Agnew, William S.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 2006, 64 (02) : 320 - 342

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