This report describes
muscular dystrophy, limb-girdle, autosomal dominant 3 (LGMDD3). The human gene implicated in this disease is HNRNPDL, an RNA-binding protein involved in mRNA biogenesis. There is a single high-ranking ortholog of HNRNPDL in Drosophila, sqd. Several alleles have been generated for sqd, including alleles carrying RNAi targeting constructs and generated by insertional mutagenesis.
HNRNPDL is also one of the genes removed in the 4q21 microdeletion, which has a pathogenic phenotype (MIM:613509).
The human gene Hsap\HNRNPDL has been introduced into flies, both as a wild-type allele and two disease-associated variants.
Mutations at amino acid 378 (as measured in the longest isoform) of HNRNPDL have been associated with LGMDD3 in humans, which places them within HNRNPDL's prion-like domain. Flies expressing disease-associated mutant alleles (HNRNPDL p.Asp295Asn and p.Asp295His, corresponding to p.Asp378Asn and p.Asp378His in the longest isoform) in flight muscle show mildly disorganized muscle fibers. More importantly, the HNRNPDL mutant proteins are found in the detergent-insoluble fraction of flight muscle samples, evidence of enhanced protein aggregation.
[updated Mar. 2020 by FlyBase; FBrf0222196]
[MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 3; LGMDD3](https://omim.org/entry/609115)
[HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN D-LIKE PROTEIN; HNRNPDL](https://omim.org/entry/607137)
Currently, the term LGMD refers to a group of genetically heterogeneous, autosomally inherited muscular dystrophies that share a common phenotype consisting of: progressive weakness and wasting of hip- or shoulder-girdle muscles; onset after 2 years of life; varying degrees of creatine kinase (CK) elevation, ranging from normal to markedly elevated; and variable pathologic findings, ranging from nonspecific myopathic changes to dystrophic features. (From Llewluck and Milone 2018, pubmed:29350766.)
Autosomal dominant limb-girdle muscular dystrophy-3 is characterized by slowly progressive proximal muscle weakness affecting the upper and lower limbs. Onset is usually in adulthood, but can occur during the teenage years. Affected individuals may also develop cataracts before age 50 (summary by Vieira et al. 2014, pubmed:24647604). [from MIM:609115, 2020.03.10]
Genome sequencing of Brazilian, Chinese, Uruguayan, and Argentinian families affected by limb-girdle muscular dystrophy 1G (LGMD1G, or LGMDD3 in the new nomenclature) detected D378N and D378H point substitutions in HNRNPDL, indicating a mutation hotspot for this disease. (From Batlle et al. 2020 and references therein, FBrf0244684.)
In affected members of a Brazilian family and a Uruguayan family with LGMD1G, Vieira et al.2014 (pubmed:24647604) identified 2 different heterozygous missense mutations affecting the same codon in the HNRNPDL gene (D378N, MIM:607137.0001 and D378H, MIM:607137.0002, respectively). The mutations were found by a combination of linkage analysis and whole-genome sequencing. [from MIM:609115, 2020.03.10]
The HNRNPDL gene contains nine exons and eight introns, and three isoforms are produced by alternative splicing. DL2 was the first isoform discovered as a JKT41 binding protein 1 (JKTBP1) and it is the predominant isoform in all mouse and human tissues. It is 301 amino acids long, constituted by two contiguous canonical RNA recognition motifs (RRMs) and one predicted prion-like domain at the C terminus, enriched in Gly and Tyr residues. DL1 is a longer isoform of 420 amino acids comprising an additional predicted to be disordered and Arg-enriched domain at the N terminus. DL1 expression levels are 4-fold lower than those of DL2 and the transcript is mainly present in brain and testis. DL3 is the shorter and minor isoform, with only 244 amino acids missing both N and C terminus disordered regions. (Adapted from Batlle et al. 2020 and references therein, FBrf0244684.)
Many to one: three human genes to one Drosophila gene.
Single, high-ranking ortholog of human Hsap\HNRNPDL. sqd is orthologous to three human paralogs: Hsap\HNRNPDL, HNRNPAB, and HNRNPD.
