Key result
HNRPDL mutations cause limb-girdle muscular dystrophy 1G by impairing muscle development in preclinical models.
Mutations in the RNA-processing protein HNRPDL cause limb-girdle muscular dystrophy 1G, demonstrating a novel association between a muscular disorder and an RNA-related gene.
Should not yet change LGMD practice; leaves open HNRPDL's role pending human validation.
Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. More than 20 genes with autosomal recessive (LGMD2A to LGMD2Q) and autosomal dominant inheritance (LGMD1A to LGMD1H) have been mapped/identified to date. Mutations are known for six among the eight mapped autosomal dominant forms: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin-3), LGMD1D (desmin), LGMD1E (DNAJB6), and more recently for LGMD1F (transportin-3). Our group previously mapped the LGMD1G gene at 4q21 in a Caucasian-Brazilian family. We now mapped a Uruguayan family with patients displaying a similar LGMD1G phenotype at the same locus. Whole genome sequencing identified, in both families, mutations in the HNRPDL gene. HNRPDL is a heterogeneous ribonucleoprotein family member, which participates in mRNA biogenesis and metabolism. Functional studies performed in S. cerevisiae showed that the loss of HRP1 (yeast orthologue) had pronounced effects on both protein levels and cell localizations, and yeast proteome revealed dramatic reorganization of proteins involved in RNA-processing pathways. In vivo analysis showed that hnrpdl is important for muscle development in zebrafish, causing a myopathic phenotype when knocked down. The present study presents a novel association between a muscular disorder and a RNA-related gene and reinforces the importance of RNA binding/processing proteins in muscle development and muscle disease. Understanding the role of these proteins in muscle might open new therapeutic approaches for muscular dystrophies.
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Vieira et al. (2014) studied Limb-girdle muscular dystrophy 1G (LGMD1G). HNRPDL gene mutations was evaluated on Identification of genetic mutations and functional characterization. Mutations in the RNA-processing gene HNRPDL cause limb-girdle muscular dystrophy 1G (LGMD1G), with functional studies in yeast and zebrafish confirming its importance in muscle development.
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