L.I.1: Autosomal dominant limb-girdle muscular dystrophies

Abstract

The first gene identified in the group of autosomal dominant forms of LGMD was CAV3 more than 15 years ago, although families with caveolinopathy LGMD1C have remained very rare in the total group of LGMD families. In 2000 two more genes were identified: MYOT in LGMD1A and LMNA in LGMD1B. The LGMD phenotype of Myotilinopathy has also remained very rare, whereas mutations in MYOT much more frequently cause late onset distal myopathy with the characteristic myofibrillar pathology. Laminopathies however are not rare and present with a large range of different phenotypes. Pure LGMD may be less common than autosomal dominant EDMD and these two phenotypes may variably be present even within the families. The chromosomal locus definitions of 7q36 and 6q23 linked LGMD1D and LGMD1E have been mixed up constantly over the years, but since the original family linked to 6q23 recently proved to be desminopathy, there is no 6q23 linked autosomal dominant LGMD anymore and thus the 7q36 linked disease is LGMD1D, which also corresponds to the HGNC definition. The mutated gene in LGMD1D encodes a ubiquitously expressed co-chaperone DNAJB6. The latest gene identification was TNPO3 responsible for LGMD1F. One very interesting feature with this collection of dominant LGMD genes is that there is no obvious common denominator for the functions of the proteins: Myotilin is a Z-disc protein, Lamin A/C is in the nuclear envelope, Caveolin-3 in the caveolae of the sarcolemma, DNAJB6 is a component of the chaperonal maintenance machinery, and Transportin-3 in the nuclear membrane pores. Other autosomal dominant LGMD families still await the identification of the responsible gene defects. The first gene identified in the group of autosomal dominant forms of LGMD was CAV3 more than 15 years ago, although families with caveolinopathy LGMD1C have remained very rare in the total group of LGMD families. In 2000 two more genes were identified: MYOT in LGMD1A and LMNA in LGMD1B. The LGMD phenotype of Myotilinopathy has also remained very rare, whereas mutations in MYOT much more frequently cause late onset distal myopathy with the characteristic myofibrillar pathology. Laminopathies however are not rare and present with a large range of different phenotypes. Pure LGMD may be less common than autosomal dominant EDMD and these two phenotypes may variably be present even within the families. The chromosomal locus definitions of 7q36 and 6q23 linked LGMD1D and LGMD1E have been mixed up constantly over the years, but since the original family linked to 6q23 recently proved to be desminopathy, there is no 6q23 linked autosomal dominant LGMD anymore and thus the 7q36 linked disease is LGMD1D, which also corresponds to the HGNC definition. The mutated gene in LGMD1D encodes a ubiquitously expressed co-chaperone DNAJB6. The latest gene identification was TNPO3 responsible for LGMD1F. One very interesting feature with this collection of dominant LGMD genes is that there is no obvious common denominator for the functions of the proteins: Myotilin is a Z-disc protein, Lamin A/C is in the nuclear envelope, Caveolin-3 in the caveolae of the sarcolemma, DNAJB6 is a component of the chaperonal maintenance machinery, and Transportin-3 in the nuclear membrane pores. Other autosomal dominant LGMD families still await the identification of the responsible gene defects.