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

Joachim Schessl, Yaqun Zou, Meagan Jane Mcgrath, Belinda Simone Cowling, Baijayanta Maiti, Steven S Chin, Caroline Sewry, Roberta Battini, Ying Hu, Denny Cottle, Michael Rosenblatt, Lynn Spruce, Arupa Ganguly, Janbernd Kirschner, Alexander R Judkins, Jeffrey A Golden, Hans-Hilmar Goebel, Francesco Muntoni, Kevin M Flanigan, Christina Anne Mitchell & 1 others Carsten G Bonnemann

Research output: Contribution to journalArticleResearchpeer-review

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 microdissection/proteomics approach has helped identify both inherited and de novo mutations in FHL1, thereby defining a new X-linked protein aggregation disorder of muscle.
Original languageEnglish
Pages (from-to)904 - 912
Number of pages9
JournalJournal of Clinical Investigation
Volume118
Issue number3
Publication statusPublished - 2008

Cite this

Schessl, J., Zou, Y., Mcgrath, M. J., Cowling, B. S., Maiti, B., Chin, S. S., ... Bonnemann, C. G. (2008). Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy. Journal of Clinical Investigation, 118(3), 904 - 912.
Schessl, Joachim ; Zou, Yaqun ; Mcgrath, Meagan Jane ; Cowling, Belinda Simone ; Maiti, Baijayanta ; Chin, Steven S ; Sewry, Caroline ; Battini, Roberta ; Hu, Ying ; Cottle, Denny ; Rosenblatt, Michael ; Spruce, Lynn ; Ganguly, Arupa ; Kirschner, Janbernd ; Judkins, Alexander R ; Golden, Jeffrey A ; Goebel, Hans-Hilmar ; Muntoni, Francesco ; Flanigan, Kevin M ; Mitchell, Christina Anne ; Bonnemann, Carsten G. / Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 3. pp. 904 - 912.
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title = "Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy",
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 microdissection/proteomics approach has helped identify both inherited and de novo mutations in FHL1, thereby defining a new X-linked protein aggregation disorder of muscle.",
author = "Joachim Schessl and Yaqun Zou and Mcgrath, {Meagan Jane} and Cowling, {Belinda Simone} and Baijayanta Maiti and Chin, {Steven S} and Caroline Sewry and Roberta Battini and Ying Hu and Denny Cottle and Michael Rosenblatt and Lynn Spruce and Arupa Ganguly and Janbernd Kirschner and Judkins, {Alexander R} and Golden, {Jeffrey A} and Hans-Hilmar Goebel and Francesco Muntoni and Flanigan, {Kevin M} and Mitchell, {Christina Anne} and Bonnemann, {Carsten G}",
year = "2008",
language = "English",
volume = "118",
pages = "904 -- 912",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
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Schessl, J, Zou, Y, Mcgrath, MJ, Cowling, BS, Maiti, B, Chin, SS, Sewry, C, Battini, R, Hu, Y, Cottle, D, Rosenblatt, M, Spruce, L, Ganguly, A, Kirschner, J, Judkins, AR, Golden, JA, Goebel, H-H, Muntoni, F, Flanigan, KM, Mitchell, CA & Bonnemann, CG 2008, 'Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy' Journal of Clinical Investigation, vol. 118, no. 3, pp. 904 - 912.

Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy. / Schessl, Joachim; Zou, Yaqun; Mcgrath, Meagan Jane; Cowling, Belinda Simone; Maiti, Baijayanta; Chin, Steven S; Sewry, Caroline; Battini, Roberta; Hu, Ying; Cottle, Denny; Rosenblatt, Michael; Spruce, Lynn; Ganguly, Arupa; Kirschner, Janbernd; Judkins, Alexander R; Golden, Jeffrey A; Goebel, Hans-Hilmar; Muntoni, Francesco; Flanigan, Kevin M; Mitchell, Christina Anne; Bonnemann, Carsten G.

In: Journal of Clinical Investigation, Vol. 118, No. 3, 2008, p. 904 - 912.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy

AU - Schessl, Joachim

AU - Zou, Yaqun

AU - Mcgrath, Meagan Jane

AU - Cowling, Belinda Simone

AU - Maiti, Baijayanta

AU - Chin, Steven S

AU - Sewry, Caroline

AU - Battini, Roberta

AU - Hu, Ying

AU - Cottle, Denny

AU - Rosenblatt, Michael

AU - Spruce, Lynn

AU - Ganguly, Arupa

AU - Kirschner, Janbernd

AU - Judkins, Alexander R

AU - Golden, Jeffrey A

AU - Goebel, Hans-Hilmar

AU - Muntoni, Francesco

AU - Flanigan, Kevin M

AU - Mitchell, Christina Anne

AU - Bonnemann, Carsten G

PY - 2008

Y1 - 2008

N2 - 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 microdissection/proteomics approach has helped identify both inherited and de novo mutations in FHL1, thereby defining a new X-linked protein aggregation disorder of muscle.

AB - 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 microdissection/proteomics approach has helped identify both inherited and de novo mutations in FHL1, thereby defining a new X-linked protein aggregation disorder of muscle.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18274675

M3 - Article

VL - 118

SP - 904

EP - 912

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 3

ER -