title: A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G).
abstract: 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.
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil Program in Genomics, Department of Pediatrics and The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA, USA Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Natássia M
authors.initials: NM
authors.lastname: Vieira
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Michel S
authors.initials: MS
authors.lastname: Naslavsky
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Licinio
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil Department of Neurology, University of São Paulo Medical School, São Paulo, Brazil Mendelics Análise Genômica, São Paulo, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil Mendelics Análise Genômica, São Paulo, Brazil Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: David
authors.initials: D
authors.lastname: Schlesinger
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Mariz
authors.initials: M
authors.lastname: Vainzof
authors.affiliation: Hospital de Clínicas, Montevideu, Montevideo, Uruguay.
authors.forename: Nury
authors.initials: N
authors.lastname: Sanchez
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil Mendelics Análise Genômica, São Paulo, Brazil.
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Kitajima
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Lihi
authors.initials: L
authors.lastname: Gal
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Natale
authors.initials: N
authors.lastname: Cavaçana
authors.affiliation: Program in Genomics, Department of Pediatrics and The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA, USA Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Serafini
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Silvia
authors.initials: S
authors.lastname: Chuartzman
authors.affiliation: Hospital de Clínicas, Montevideu, Montevideo, Uruguay.
authors.forename: Cristina
authors.initials: C
authors.lastname: Vasquez
authors.affiliation: Department of Genetics, Clemente Estabele Institute, Montevideo, Uruguay.
authors.forename: Adriana
authors.initials: A
authors.lastname: Mimbacas
authors.affiliation: TIGEM (Telethon Institute of Genetics and Medicine), Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nigro
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
authors.forename: Rita C
authors.initials: RC
authors.lastname: Pavanello
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Schuldiner
authors.affiliation: Program in Genomics, Department of Pediatrics and The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA, USA Department of Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Kunkel
authors.affiliation: Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil mayazatz@usp.br.
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
mesh_terms: D000328:Adult; D000818:Animals; D002874:Chromosome Mapping; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012323:RNA Processing, Post-Transcriptional; D012261:Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C111986:HNRPDL protein, human; C512636:HRP1 protein, S cerevisiae; D012261:Ribonucleoproteins; D029701:Saccharomyces cerevisiae Proteins; D039221:mRNA Cleavage and Polyadenylation Factors