Vieira Natássia M, Naslavsky Michel S, Licinio Luciana, Kok Fernando, Schlesinger David, Vainzof Mariz, Sanchez Nury, Kitajima João Paulo, Gal Lihi, Cavaçana Natale, Serafini Peter R, Chuartzman Silvia, Vasquez Cristina, Mimbacas Adriana, Nigro Vincenzo, Pavanello Rita C, Schuldiner Maya, Kunkel Louis M, Zatz Mayana
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.
Human Genome and Stem Cell Center, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
Hum Mol Genet. 2014 Aug 1;23(15):4103-10. doi: 10.1093/hmg/ddu127. Epub 2014 Mar 18.
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.
肢带型肌营养不良症（LGMD）是一组由基因决定的异质性肌肉疾病，主要或主要累及骨盆或肩胛带肌肉组织。迄今为止，已定位/鉴定出20多个具有常染色体隐性遗传（LGMD2A至LGMD2Q）和常染色体显性遗传（LGMD1A至LGMD1H）的基因。在已定位的8种常染色体显性遗传形式中，已知6种存在突变：LGMD1A（肌联蛋白）、LGMD1B（核纤层蛋白A/C）、LGMD1C（小窝蛋白-3）、LGMD1D（结蛋白）、LGMD1E（DNAJB6），最近还发现LGMD1F（转运蛋白-3）存在突变。我们的研究小组先前在一个巴西白人家族中将LGMD1G基因定位到4q21。我们现在在一个乌拉圭家族中也将表现出类似LGMD1G表型的患者定位到了同一基因座。全基因组测序在这两个家族中均鉴定出HNRPDL基因存在突变。HNRPDL是一种异质性核糖核蛋白家族成员，参与mRNA的生物合成和代谢。在酿酒酵母中进行的功能研究表明，HRP1（酵母同源物）的缺失对蛋白质水平和细胞定位均有显著影响，酵母蛋白质组显示参与RNA加工途径的蛋白质发生了显著重组。体内分析表明，hnrpdl对斑马鱼的肌肉发育很重要，敲低该基因会导致肌病表型。本研究揭示了一种肌肉疾病与一个RNA相关基因之间的新关联，并强化了RNA结合/加工蛋白在肌肉发育和肌肉疾病中的重要性。了解这些蛋白在肌肉中的作用可能会为肌营养不良症开辟新的治疗途径。
