von Spiczak Sarah, Helbig Katherine L, Shinde Deepali N, Huether Robert, Pendziwiat Manuela, Lourenço Charles, Nunes Mark E, Sarco Dean P, Kaplan Richard A, Dlugos Dennis J, Kirsch Heidi, Slavotinek Anne, Cilio Maria R, Cervenka Mackenzie C, Cohen Julie S, McClellan Rebecca, Fatemi Ali, Yuen Amy, Sagawa Yoshimi, Littlejohn Rebecca, McLean Scott D, Hernandez-Hernandez Laura, Maher Bridget, Møller Rikke S, Palmer Elizabeth, Lawson John A, Campbell Colleen A, Joshi Charuta N, Kolbe Diana L, Hollingsworth Georgie, Neubauer Bernd A, Muhle Hiltrud, Stephani Ulrich, Scheffer Ingrid E, Pena Sérgio D J, Sisodiya Sanjay M, Helbig Ingo
Author affiliations are provided at the end of the article.
Neurology. 2017 Jul 25;89(4):385-394. doi: 10.1212/WNL.0000000000004152. Epub 2017 Jun 30.
To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.
We reviewed phenotypic data of 21 patients (7 previously published) with mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.
We identified 19 patients with de novo mutations in and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.
The phenotypic spectrum of -related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.
评估由编码突触前蛋白DNM1的发动蛋白1（DNM1）突变引起的表型谱，并基于结构建模研究可能的基因型-表型相关性及预测的功能后果。
我们回顾了21例（7例先前已发表）患有DNM1突变患者的表型数据。我们将突变数据与已知的功能数据进行比较，并进行生物分子建模以评估突变对蛋白质功能的影响。
我们鉴定出19例患有DNM1新生突变的患者以及一对从嵌合型父母那里遗传了突变的同胞。7例患者（33.3%）携带复发性p.Arg237Trp突变。出现了一种常见的表型，包括所有患者均有严重至极重度智力残疾和肌张力减退，21例患者中有16例患有以婴儿痉挛为特征的癫痫，且常演变为Lennox-Gastaut综合征。2例患者有严重的全面发育迟缓但无癫痫发作。此外，我们描述了1例在灾难性癫痫发作前发育正常的患者，符合4岁时的热性感染相关性癫痫综合征。所有突变均聚集在GTP酶或中间结构域内，结构建模和现有功能数据表明对DNM1功能有显性负性作用。
与许多其他遗传性癫痫不同，DNM1相关脑病的表型谱相对一致。高达三分之一的患者携带复发性p.Arg237Trp变异体，该变异体现已成为迄今为止在癫痫性脑病中鉴定出的最常见的复发性变异体之一。鉴于该突变预测的显性负性机制，该变异体是治疗干预的主要靶点。
