Segregation between SMCHD1 mutation, D4Z4 hypomethylation and Facio-Scapulo-Humeral Dystrophy: a case report

BMC Medical Genetics

Case Report

Catherine Vovan¹  Charlene Chaix¹  Marie-Cécile Gaillard²  Camille Dion²  Frédérique Magdinier²  Stéphane Roche²  Killian Mazaleyrat²  Francesca Puppo²  Armand Tasmadjian²  Shahram Attarian³  Emmanuelle Salort Campana³  Nicolas Lévy⁴  Rafaelle Bernard⁴  Marc Bartoli⁴  Karine Nguyen⁴  Virginie Mariot⁵  Julie Dumonceaux⁵ 

[1] APHM, Laboratoire de Génétique Médicale, Hôpital de la Timone, 13385, Marseille, France;Aix Marseille Univ, INSERM, GMGF, Marseille, France;Aix Marseille Univ, INSERM, GMGF, Marseille, France;APHM, Centre de Référence des Maladies Neuromusculaires et de la SLA, Hôpital de la Timone, 13385, Marseille, France;Aix Marseille Univ, INSERM, GMGF, Marseille, France;APHM, Laboratoire de Génétique Médicale, Hôpital de la Timone, 13385, Marseille, France;Center of Research in Myology/ Institut de Myologie UMR974 - UPMC Université Paris 6/ Inserm /FRE3617– CNRS, Groupement Hospitalier de la Pitié Salpétrière, Cedex 13, Paris, France;

关键词: Facio-Scapulo-Humeral Dystrophy;    DNA methylation;    SMCHD1;    DNA combing;    Haploinsufficiency;    DUX4;   

DOI  :  10.1186/s12881-016-0328-9

 received in 2016-02-09, accepted in 2016-09-09,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe main form of Facio-Scapulo-Humeral muscular Dystrophy is linked to copy number reduction of the 4q D4Z4 macrosatellite (FSHD1). In 5 % of cases, FSHD phenotype appears in the absence of D4Z4 reduction (FSHD2). In 70-80 % of these patients, variants of the SMCHD1 gene segregate with 4qA haplotypes and D4Z4 hypomethylation.Case presentationWe report a family presenting with neuromuscular symptoms reminiscent of FSHD but without D4Z4 copy reduction. We characterized the 4q35 region using molecular combing, searched for mutation in the SMCHD1 gene and determined D4Z4 methylation level by sodium bisulfite sequencing. We further investigated the impact of the SMCHD1 mutation at the protein level and on the NMD-dependent degradation of transcript.In muscle, we observe moderate but significant reduction in D4Z4 methylation, not correlated with DUX4-fl expression. Exome sequencing revealed a heterozygous insertion of 7 bp in exon 37 of the SMCHD1 gene producing a loss of frame with premature stop codon 4 amino acids after the insertion (c.4614-4615insTATAATA). Both wild-type and mutated transcripts are detected.ConclusionThe truncated protein is absent and the full-length protein level is similar in patients and controls indicating that in this family, FSHD is not associated with SMCHD1 haploinsufficiency.

【 授权许可】

CC BY   
© The Author(s). 2016