Abstract:

Facioscapulohumeral muscular dystrophy 2 (FSHD2) is a genetic muscular disorder characterized by DNA hypomethylation on the 4q-subtelomeric macrosatellite repeat array, D4Z4. FSHD2 is caused by heterozygous mutations in the gene encoding structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1). Because there has been no study on FSHD2 in Asian populations, it is not known whether this disease mechanism is widely seen. To identify FSHD2 patients with SMCHD1 mutations in the Japanese population, bisulfite pyrosequencing was used to measure DNA methylation on the D4Z4 repeat array, and in patients with DNA hypomethylation, the SMCHD1 gene was sequenced by the Sanger method. Twenty patients with D4Z4 hypomethylation were identified. Of these, 13 patients from 11 unrelated families had ten novel and one reported SMCHD1 mutations: four splice-site, two nonsense, two in-frame deletion, two out-of-frame deletion, and one missense mutations. One of the splice-site mutations was homozygous in the single patient identified with this. In summary, we identified novel SMCHD1 mutations in a Japanese cohort of FSHD2 patients, confirming the presence of this disease in a wider population than previously known.

日本語要旨:

本研究で、アジア人初の顔面肩甲上腕型筋ジストロフィー2型(FSHD2)患者が同定された。FSHDは、D4Z4リピートと呼ばれる繰り返しDNA配列が短縮して発症するFSHD1と、SMCHD1と呼ばれる遺伝子の変異で発症するFSHD2に分類される。今まで、アジア人のFSHD2患者の報告はなかった。本研究では、SMCHD1遺伝子における変異を持つ日本人患者11家系13症例が同定された。結果、これらFSHD2患者は、FSHD1と臨床的、 筋病理学的に同様であった。また遺伝学的に、日本人FSHD2患者は、欧米のFSHD2患者と異なる種類のSMCHD1遺伝子変異を持っていた。また、これらFSHD2患者はD4Z4リピートが正常下限程度の長さであり、SMCHD1遺伝子変異のみならずD4Z4リピートがある程度短い事がFSHD2発症に必要である可能性が示唆された。