De Cid Rafael, Ben Yaou Rabah, Roudaut Carinne, Charton Karine, Baulande Sylvain, Leturcq France, Romero Norma Beatriz, Malfatti Edoardo, Beuvin Maud, Vihola Anna, Criqui Audrey, Nelson Isabelle, Nectoux Juliette, Ben Aim Laurène, Caloustian Christophe, Olaso Robert, Udd Bjarne, Bonne Gisèle, Eymard Bruno, Richard Isabelle
From INSERM (R.D.C., C.R., K.C., I.R.), U951; Généthon (R.D.C., C.R., K.C., I.R.), R&D Department, INTEGRARE Research Unit, Evry; Neuromuscular Morphology Unit, Myology Institute (N.B.R., M.B.), and INSERM UMRS_974, CNRS FRE 3617, Center of Research in Myology (R.B.Y., F.L., N.B.R., E.M., M.B., I.N., G.B.), Sorbonne Universités, UPMC Univ Paris 06, and AP-HP, University Hospital, Reference Center for Neuromuscular Diseases, Myology Institute (R.B.Y., N.B.R., E.M., B.E.), Groupe Hospitalier La Pitié-Salpêtrière, Paris; Génopole Campus 2 (S.B., A.C.), PartnerChip, Evry; the Department of Medical Genetics (F.L., A.V., B.U.), Folkhälsan Institute of Genetics, University of Helsinki, Finland; AP-HP (J.N.), Groupe Hospitalier Cochin-Broca-Hôtel Dieu, Laboratoire de Biochimie et Génétique Moléculaire, Paris; CEA-IG-Centre National de Genotypage (L.B.A., C.C., R.O.), Evry; Neuromuscular Research Center (B.U.), Tampere University Hospital and University of Tampere, Finland; and the Department of Neurology (B.U.), Vaasa Central Hospital, Finland. R.D.C. is currently affiliated with Disease Genomics Group, Institut de Medicina Predictiva i Personalitzada del Càncer, Campus de Can Ruti, Camí de les Escoles, Badalona (Barcelona), Spain.
Neurology. 2015 Dec 15;85(24):2126-35. doi: 10.1212/WNL.0000000000002200. Epub 2015 Nov 18.
To identify the genetic defects present in 3 families with muscular dystrophy, contractures, and calpain 3 deficiency.
We performed targeted exome sequencing on one patient presenting a deficiency in calpain 3 on Western blot but for which mutations in the gene had been excluded. The identification of a homozygous truncating mutation in the M-line part of titin prompted us to sequence this region in 2 additional patients presenting similar clinical and biochemical characteristics.
The 3 patients shared similar features: coexistence of limb-girdle weakness and early-onset diffuse joint contractures without cardiomyopathy. The biopsies showed rimmed vacuoles, a dystrophic pattern, and secondary reduction in calpain 3. We identified a novel homozygous mutation in the exon Mex3 of the TTN gene in the first patient. At protein level, this mutation introduces a stop codon at the level of Mex3. Interestingly, we identified truncating mutations in both alleles in the same region of the TTN gene in patients from 2 additional families. Molecular protein analyses confirm loss of the C-ter part of titin.
Our study broadens the phenotype of titinopathies with the report of a new clinical entity with prominent contractures and no cardiac abnormality and where the recessive mutations lead to truncation of the M-line titin and secondary calpain 3 deficiency.
鉴定3个患有肌肉萎缩症、挛缩和钙蛋白酶3缺乏症的家庭中存在的基因缺陷。
我们对一名在蛋白质免疫印迹法检测中显示钙蛋白酶3缺乏但基因中未发现突变的患者进行了靶向外显子组测序。在肌联蛋白M线部分鉴定出一个纯合截短突变，促使我们对另外2名具有相似临床和生化特征的患者的该区域进行测序。
这3名患者具有相似特征：存在肢带肌无力和早发性弥漫性关节挛缩，且无心肌病。活检显示有镶边空泡、营养不良模式以及钙蛋白酶3继发性减少。我们在首例患者的TTN基因外显子Mex3中鉴定出一个新的纯合突变。在蛋白质水平上，该突变在Mex3处引入了一个终止密码子。有趣的是，我们在另外2个家庭的患者的TTN基因同一区域的两个等位基因中都鉴定出了截短突变。分子蛋白质分析证实肌联蛋白C端部分缺失。
我们的研究拓宽了肌联蛋白病的表型，报道了一种新的临床实体，其具有明显的挛缩且无心脏异常，隐性突变导致M线肌联蛋白截短和继发性钙蛋白酶3缺乏。
