Molecular and clinical descriptions of patients with GABAA receptor gene variants (GABRA1, GABRB2, GABRB3, GABRG2): A cohort study, review of literature, and genotype-phenotype correlation

被引：42

作者：

Maillard, Pierre-Yves ^{[1
]}

Baer, Sarah ^{[2
,3
]}

Schaefer, Elise ^{[1
]}

Desnous, Beatrice ^{[4
]}

Villeneuve, Nathalie ^{[4
]}

Lepine, Anne ^{[4
]}

Fabre, Alexandre ^{[5
,6
]}

Lacoste, Caroline ^{[7
]}

El Chehadeh, Salima ^{[1
,3
]}

Piton, Amelie ^{[3
,8
]}

Porter, Louise Frances ^{[9
]}

Perriard, Caroline ^{[2
]}

Warde, Marie-Therese Abi ^{[2
]}

Spitz, Marie-Aude ^{[2
]}

Laugel, Vincent ^{[2
]}

Lesca, Gaetan ^{[10
]}

Putoux, Audrey ^{[10
]}

Ville, Dorothee ^{[11
,12
]}

Mignot, Cyril ^{[13
,14
,15
]}

Heron, Delphine ^{[13
,14
,15
]}

Nabbout, Rima ^{[16
]}

Barcia, Giulia ^{[17
]}

Rio, Marlene ^{[17
]}

Roubertie, Agathe ^{[18
]}

Meyer, Pierre ^{[18
]}

Paquis-Flucklinger, Veronique ^{[19
]}

Patat, Olivier ^{[20
]}

Lefranc, Jeremie ^{[21
]}

Gerard, Marion ^{[22
]}

de Bellescize, Julietta ^{[23
]}

Villard, Laurent ^{[5
,24
]}

De Saint Martin, Anne ^{[2
,3
]}

Milh, Mathieu ^{[24
]}

机构：

[1] Hop Univ Strasbourg, Dept Med Genet, IGMA, Strasbourg, France

[2] Hop Univ Strasbourg, Dept Neuropediat, ERN EpiCare, Strasbourg, France

[3] Univ Strasbourg, Inst Genet & Mol & Cellular Biol IGBMC, CNRS, UMR7104,INSERM,U1258, Illkirch Graffenstaden, France

[4] La Timone Childrens Hosp, AP HM, Dept Pediat Neurol, Marseille, France

[5] Timone Enfant, AP HM, Pediat Multidisciplinary Unit, Marseille, France

[6] Aix Marseille Univ, INSERM, GMGF, Marseille, France

[7] La Timone Childrens Hosp, Dept Med Genet, Marseille, France

[8] Hop Univ Strasbourg, Inst Genet Med Alsace, Lab Genet Diag, Strasbourg, France

[9] Inst Genet Med Alsace, Ctr Reference Affect Rares Genet Ophtalmol CARGO, Dept Med Genet, Strasbourg, France

[10] Hosp Civils Lyon, Dept Genet, Bron, France

[11] Lyon Univ Hosp, Mother Child Womens Hosp, Pediat Neurol Dept, Lyon, France

[12] Lyon Univ Hosp, Mother Child Womens Hosp, Reference Ctr Rare Epilepsies, Lyon, France

[13] Sorbonne Univ, Grp Hosp Pitie Salpetriere, Dept Genet, Paris, France

[14] Sorbonne Univ, Hop Armand Trousseau, AP HP, Paris, France

[15] Ctr Reference Deficiences Intellectuelles Causes, Paris, France

[16] Univ Paris, Necker Enfants Malades Univ Hosp, AP HP, Dept Pediat Neurol,Reference Ctr Rare Epilepsies, Paris, France

[17] Univ Paris, Necker Enfants Malades Hosp, Dept Med Genet, Paris, France

[18] Univ Montpellier, CHU Montpellier, INSERM, Pediat Neurol Dept,INM, Montpellier, France

[19] Nice Univ Hosp, Dept Med Genet, Nice, France

[20] CHU Toulouse Purpan, Dept Med Genet, Toulouse, France

[21] CHU Brest, Pediat Dept, Brest, France

[22] Ctr Hosp Univ Caen, Dept Med Genet, Caen, France

[23] Univ Hosp Lyon HCL, Reference Ctr Rare Epilepsies, Paediat Clin Epileptol & Funct Neurol Dept, ERN EpiCARE, Lyon, France

[24] Aix Marseille Univ, Fac Medecine Timone, MMG, INSERM,U1251,ERN Epicare, Marseille, France

来源：

EPILEPSIA | 2022年 / 63卷 / 10期

关键词：

channelopathy; developmental and epileptic encephalopathy; GABA A receptor; genetic generalized epilepsy; MUTATIONS; EPILEPSY; SUBUNIT; GAMMA-2-SUBUNIT; PREDICTION;

D O I：

10.1111/epi.17336

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: gamma-Aminobutyric acid (GABA)(A)-receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABA(A)-receptor-related disorders as a whole and seek possible genotype-phenotype correlations. Methods: We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABA(A)-receptor subunit variants (GABRA1, GABRB2, GABRB3, and GABRG2) through a national French collaboration using the EPIGENE network and compared these data to the one already described in the literature. Results: We gathered the reported patients in three epileptic phenotypes: 15 patients with fever-related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABA(A)-receptor subunit gene, whereas N-terminal variants seemed to be related to milder phenotypes. Significance: GABA(A)-receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes described here was associated with a specific phenotype. On the other hand, it appears that the location of the variant on the protein may be a marker of severity. Variant location may have important weight in the development of targeted therapeutics.

引用

页码：2519 / 2533

页数：15

共 1 条

[1] Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors
Hernandez, Ciria C.
Tian, XiaoJuan
Hu, Ningning
Shen, Wangzhen
Catron, Mackenzie A.
Yang, Ying
Chen, Jiaoyang
Jiang, Yuwu
Zhang, Yuehua
Macdonald, Robert L.
BRAIN COMMUNICATIONS, 2021, 3 (02)

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