Novel SUZ12 mutations in Weaver‐like syndrome

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146320/1/cge13415_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146320/2/cge13415-sup-0001-AppendixS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146320/3/cge13415.pd

Mutations in the Satellite Cell Gene MEGF10 Cause a Recessive Congenital Myopathy with Minicores

We ascertained a nuclear family in which three of four siblings were affected with an unclassified autosomal recessive myopathy characterized by severe weakness, respiratory impairment, scoliosis, joint contractures, and an unusual combination of dystrophic and myopathic features on muscle biopsy. Whole genome sequence from one affected subject was filtered using linkage data and variant databases. A single gene, MEGF10, contained nonsynonymous mutations that co-segregated with the phenotype. Affected subjects were compound heterozygous for missense mutations c.976T > C (p.C326R) and c.2320T > C (p.C774R). Screening the MEGF10 open reading frame in 190 patients with genetically unexplained myopathies revealed a heterozygous mutation, c.211C > T (p.R71W), in one additional subject with a similar clinical and histological presentation as the discovery family. All three mutations were absent from at least 645 genotyped unaffected control subjects. MEGF10 contains 17 atypical epidermal growth factor-like domains, each of which contains eight cysteine residues that likely form disulfide bonds. Both the p.C326R and p.C774R mutations alter one of these residues, which are completely conserved in vertebrates. Previous work showed that murine Megf10 is required for preserving the undifferentiated, proliferative potential of satellite cells, myogenic precursors that regenerate skeletal muscle in response to injury or disease. Here, knockdown of megf10 in zebrafish by four different morpholinos resulted in abnormal phenotypes including unhatched eggs, curved tails, impaired motility, and disorganized muscle tissue, corroborating the pathogenicity of the human mutations. Our data establish the importance of MEGF10 in human skeletal muscle and suggest satellite cell dysfunction as a novel myopathic mechanism

スマートフォン ト インターネット オ モチイタ トクシマ ケンリツ カイフ ビョウイン エンカク イリョウ シエン システム k-support ノ ドウニュウ

Because a specialist in general medical treatment lacked the Kaifu area of South Tokushima absolutely, we forced a limited doctor to many burdens and performed medical treatment while I always carried risks on my back for the disease except the specialty domain. A stroke specialist in particular is an absent medical depopulated area, and it is difficult to perform the rt-PA IV therapy that is a standard therapy for a stroke for the immediate nature period. Using remote video diagnosis treatment supporting system SYNAPSE ERm that was the smartphone application that FUJIFILM developed for the purpose of canceling these, we introduced smartphone and Tokushima Prefectural Kaifu Hospital remoteness medical treatment support system （k-support） by the Internet as area medical treatment support in February, 2013. This system can provide image information and patient information such as CT or the MRI to a tablet phone and the smartphone of Tokushima Prefectural Kaifu Hospital full-time employment doctors and the doctors who support it, and work in a House in real time. In other words, we can obtain necessary information without asking the when and where and can send appropriate instructions, advice to the Tokushima Prefectural Kaifu Hospital medical attendant from a specialist for it. After introduction, the treatment with this system in 58 emergency patients was carried out in seven months until August 31. The example letting the wide area present the smartphone such as this system and a remote medical treatment support system using the Internet in the medical depopulated area is the first trial in this country

ミトコンドリア形態異常を伴う先天性筋ジストロフィーはホスファチジルコリンde novo 合成酵素欠損により起こる

京都大学0048新制・論文博士博士(医学)乙第12618号論医博第2038号新制||医||990(附属図書館)29188(主査)教授 平家 俊男, 教授 萩原 正敏, 教授 戸口田 淳也学位規則第4条第2項該当Doctor of Medical ScienceKyoto UniversityDA

Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with alpha-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD

Tandem-genotypes: robust detection of tandem repeat expansions from long DNA reads

Abstract Tandemly repeated DNA is highly mutable and causes at least 31 diseases, but it is hard to detect pathogenic repeat expansions genome-wide. Here, we report robust detection of human repeat expansions from careful alignments of long but error-prone (PacBio and nanopore) reads to a reference genome. Our method is robust to systematic sequencing errors, inexact repeats with fuzzy boundaries, and low sequencing coverage. By comparing to healthy controls, we prioritize pathogenic expansions within the top 10 out of 700,000 tandem repeats in whole genome sequencing data. This may help to elucidate the many genetic diseases whose causes remain unknown