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Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy

Schessl, J; Zou, Y; McGrath, MJ; Cowling, BS; Maiti, B; Chin, SS; Sewry, C; ... Bonnemann, CG; + view all (2008) Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy. J CLIN INVEST , 118 (3) 904 - 912. 10.1172/JCI34450.

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Abstract

Reducing body myopathy (RBM) is a rare disorder causing progressive muscular weakness characterized by aggresome-like inclusions in the myofibrils. Identification of genes responsible for RBM by traditional genetic approaches has been impossible due to the frequently sporadic occurrence in affected patients and small family sizes. As an alternative approach to gene identification, we used laser microdissection of intracytoplasmic inclusions identified in patient muscle biopsies, followed by nanoflow liquid chromatography-tandem mass spectrometry and proteomic analysis. The most prominent component of the inclusions was the Xq26.3-encoded four and a half LIM domain 1 (FHL1) protein, expressed predominantly in skeletal but also in cardiac muscle. Mutational analysis identified 4 FHL1 mutations in 2 sporadic unrelated females and in 2 families with severely affected boys and less-affected mothers. Transfection of kidney COS-7 and skeletal muscle C2C12 cells with mutant FHL1 induced the formation of aggresome-like inclusions that incorporated both mutant and wild-type FHL1 and trapped other proteins in a dominant-negative manner. Thus, a novel laser micro-dissection/proteomics approach has helped identify both inherited and de novo mutations in FHL1, thereby defining a new X-linked protein aggregation disorder of muscle.

Type: Article
Title: Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy
DOI: 10.1172/JCI34450
Keywords: LIM PROTEIN, RBP-J, CONGENITAL MYOPATHY, INCLUSION-BODIES, SKELETAL-MUSCLE, BINDING PROTEIN, KYOT2, DOMAIN, TRANSCRIPTION, AGGRESOMES
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Developmental Neurosciences Prog
URI: http://discovery.ucl.ac.uk/id/eprint/150053
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