Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A

Limb-girdle muscular dystrophies (LGMDs) are a group of inherited diseases whose genetic etiology has yet to be elucidated. The autosomal recessive forms (LGMD2) constitute a genetically heterogeneous group with LGMD2A mapping to chromosome 15q15.1-q21.1. The gene encoding the muscle-specific calcium-activated neutral protease 3 (CANP3) large subunit is located in this region. This cysteine protease belongs to the family of intracellular calpains. Fifteen nonsense, splice site, frameshift, or missense calpain mutations cosegregate with the disease in LGMD2A families, six of which were found within La Réunion island patients. A digenic inheritance model is proposed to account for the unexpected presence of multiple independent mutations in this small inbred population. Finally, these results demonstrate an enzymatic rather than a structural protein defect causing a muscular dystrophy, a defect that may have regulatory consequences, perhaps in signal transduction.

[1]  Harold Weintraub,et al.  The protein Id: A negative regulator of helix-loop-helix DNA binding proteins , 1990, Cell.

[2]  K. Campbell,et al.  Congenital muscular dystrophy with merosin deficiency. , 1994, Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie.

[3]  K. Campbell,et al.  Abnormal expression of dystrophin-associated proteins in Fukuyama-type congenital muscular dystrophy , 1993, The Lancet.

[4]  J. Concordet,et al.  Illegitimate transcription: transcription of any gene in any cell type. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[5]  K. Campbell,et al.  Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy , 1992, Nature.

[6]  A. Emery.  Population frequencies of inherited neuromuscular diseases—A world survey , 1991, Neuromuscular Disorders.

[7]  R Staden,et al.  An interactive graphics program for comparing and aligning nucleic acid and amino acid sequences. , 1982, Nucleic acids research.

[8]  J. Beckmann,et al.  A gene for limb-girdle muscular dystrophy maps to chromosome 15 by linkage. , 1991, Comptes rendus de l'Academie des sciences. Serie III, Sciences de la vie.

[9]  T. Dryja,et al.  Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. , 1994, Science.

[10]  J. Beckmann,et al.  Preferential localization of the limb-girdle muscular dystrophy type 2A gene in the proximal part of a 1-cM 15q15.1-q15.3 interval. , 1995, American journal of human genetics.

[11]  F. J. Nattrass,et al.  On the classification, natural history and treatment of the myopathies. , 1954, Brain : a journal of neurology.

[12]  K. Wang,et al.  Calmodulin-binding proteins as calpain substrates. , 1989, The Biochemical journal.

[13]  J. Beckmann,et al.  Mapping of a chromosome 15 region involved in limb girdle muscular dystrophy. , 1994, Human molecular genetics.

[14]  N. Chiannilkulchai,et al.  Regional localization of human chromosome 15 loci. , 1994, Genomics.

[15]  E. Uberbacher,et al.  Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[16]  H. Kawasaki,et al.  Muscle-specific calpain, p94, is degraded by autolysis immediately after translation, resulting in disappearance from muscle. , 1993, The Journal of biological chemistry.

[17]  H. Kawasaki,et al.  Molecular cloning of a novel mammalian calcium-dependent protease distinct from both m- and mu-types. Specific expression of the mRNA in skeletal muscle. , 1989, The Journal of biological chemistry.

[18]  S. Fields,et al.  A novel genetic system to detect protein–protein interactions , 1989, Nature.

[19]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[20]  J. Beckmann,et al.  A primary expression map of the chromosome 15q15 region containing the recessive form of limb-girdle muscular dystrophy (LGMD2A) gene. , 1995, Human molecular genetics.

[21]  J. Beckmann,et al.  Confirmation of linkage of limb-girdle muscular dystrophy, type 2, to chromosome 15. , 1992, Genomics.

[22]  S. Dimauro,et al.  Duchenne muscular dystrophy: Deficiency of dystrophin at the muscle cell surface , 1988, Cell.

[23]  J. Baker,et al.  Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r) , 1993, Cell.

[24]  Marvin B. Shapiro,et al.  RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. , 1987, Nucleic acids research.

[25]  K. Suzuki,et al.  A novel tissue-specific calpain species expressed predominantly in the stomach comprises two alternative splicing products with and without Ca(2+)-binding domain. , 1993, The Journal of biological chemistry.

[26]  K. Suzuki,et al.  Calcium activated neutral protease--structure-function relationship and functional implications. , 1990, Cell structure and function.

[27]  D. Le Paslier,et al.  Recombinations in individuals homozygous by descent localize the Friedreich ataxia locus in a cloned 450-kb interval. , 1994, American journal of human genetics.

[28]  E. Olson,et al.  A new myocyte-specific enhancer-binding factor that recognizes a conserved element associated with multiple muscle-specific genes. , 1989, Molecular and cellular biology.

[29]  C. Jackson,et al.  Progressive muscular dystrophy: autosomal recessive type. , 1961, Pediatrics.

[30]  M. Lovett,et al.  Magnetic bead capture of expressed sequences encoded within large genomic segments , 1993, Nature.

[31]  L. Kedes,et al.  Upstream regions of the human cardiac actin gene that modulate its transcription in muscle cells: presence of an evolutionarily conserved repeated motif , 1986, Molecular and cellular biology.

[32]  H. Weintraub,et al.  Differences and similarities in DNA-binding preferences of MyoD and E2A protein complexes revealed by binding site selection. , 1990, Science.

[33]  H. Kawasaki,et al.  Evolutionary origin of a calcium-dependent protease by fusion of genes for a thiol protease and a calcium-binding protein? , 1984, Nature.

[34]  H. Kawasaki,et al.  Degradation of transcription factors, c‐Jun and c‐Fos, by calpain , 1991, FEBS letters.

[35]  G. Demartino,et al.  Calcium-activated neutral protease (calpain) system: structure, function, and regulation. , 1991, Physiological reviews.

[36]  K. Suzuki,et al.  Gene structure of calcium‐dependent protease retains the ancestral organization of the calcium‐binding protein gene , 1986, FEBS letters.

[37]  J. Weissenbach,et al.  Evidence of genetic heterogeneity in the autosomal recessive adult forms of limb-girdle muscular dystrophy following linkage analysis with 15q probes in Brazilian families. , 1993, Journal of medical genetics.

[38]  T. Murachi.  Intracellular regulatory system involving calpain and calpastatin. , 1989, Biochemistry international.

[39]  J. Beckmann,et al.  Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy , 1994, Cell.

[40]  M. Kozak.  Compilation and analysis of sequences upstream from the translational start site in eukaryotic mRNAs. , 1984, Nucleic acids research.

[41]  M. Rudnicki,et al.  MyoD or Myf-5 is required for the formation of skeletal muscle , 1993, Cell.

[42]  M. Busslinger,et al.  Transcription termination and 3′ processing: the end is in site! , 1985, Cell.

[43]  S. Bhattacharya,et al.  Rapid detection of single base mismatches as heteroduplexes on Hydrolink gels. , 1991, Trends in genetics : TIG.

[44]  H. Kawasaki,et al.  Limited autolysis of calcium-activated neutral protease (CANP): reduction of the Ca2+-requirement is due to the NH2-terminal processing of the large subunit. , 1986, Journal of biochemistry.

[45]  A. Matynia,et al.  Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area. , 1993, American journal of human genetics.

[46]  K. Bushby,et al.  A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p. , 1994, Human molecular genetics.

[47]  V. Gieselmann,et al.  Multiple mutations are responsible for the high frequency of metachromatic leukodystrophy in a small geographic area. , 1995, American journal of human genetics.

[48]  R. Tjian,et al.  The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter , 1983, Cell.

[49]  P. Bucher.  Weight matrix descriptions of four eukaryotic RNA polymerase II promoter elements derived from 502 unrelated promoter sequences. , 1990, Journal of molecular biology.