Alternative titles; symbols
HGNC Approved Gene Symbol: HNRNPDL
SNOMEDCT: 719990003;
Cytogenetic location: 4q21.22 Genomic coordinates (GRCh38) : 4:82,422,564-82,430,462 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q21.22 | Muscular dystrophy, limb-girdle, autosomal dominant 3 | 609115 | Autosomal dominant | 3 |
Heterogeneous nuclear ribonucleoproteins (HNRNPs) form protein particles that bind to pre-mRNA and function in splicing and nuclear export. For further background information on HNRNPs, see HNRNPD (601324).
Doi et al. (1998) identified HNRPDL, which they called laAUF1, by differential display of leukemia cell clones showing differentiated and undifferentiated phenotypes. By screening the undifferentiated cell library and using 3-prime RACE, they obtained a cDNA encoding a deduced 271-amino acid protein containing a tyrosine phosphorylation site, 2 AU-rich element (ARE) RNA-binding motifs, and a C-terminal gln-rich motif. HNRPDL shares 73% homology with AUF1 (HNRPD) in the sequence containing the RNA-binding motifs and the gln-rich motif. Northern blot analysis revealed transcripts of approximately 1.5 and 2.4 kb.
Using an oligodeoxynucleotide, termed JKT41, corresponding to the intron 9 cis-acting element of the myeloperoxidase gene (MPO; 606989) to screen an erythroleukemia cDNA expression library, Tsuchiya et al. (1998) isolated a cDNA encoding HNRPDL, which they called JKT41-binding protein, or JKTBP. The predicted HNRPDL protein contains 302 amino acids. Northern blot analysis revealed mRNAs of approximately 1.4 and 2.8 kb expressed by most cultured cells examined.
Kamei et al. (1999) identified 2 isoforms of HNRPDL, which they called JKTBP1 and JKTBP2, corresponding to the 1.4- and 2.8-kb transcripts identified by Tsuchiya et al. (1998), respectively. The larger transcript predicts a 420-amino acid protein with a calculated molecular mass of approximately 46.4 kD. The JKTBP2 protein has a longer N terminus, and both proteins contain multiple potential sites for phosphorylation and arginine methylation. Northern blot analysis showed that both transcripts were expressed in all tissues examined, although the amounts and ratios of the transcripts varied in different tissues. Three JKTBP transcripts greater than 2.8 kb were expressed in pancreas, spleen, and thymus. Western blot analysis of myeloid leukemia cells showed proteins of 38 and 53 kD.
Doi et al. (1998) determined that HNRPDL expression was downregulated in leukemia cells following induction to proliferate with interleukin-4 (IL4; 147780) and following induction to differentiate with the phorbol ester TPA. They also found that a recombinant HNRPDL fusion protein had relatively high affinity for substrate with FOS (164810) and MYC (190080) AREs.
Tsuchiya et al. (1998) determined that recombinant HNRPDL interacted with both the double- and single-stranded forms of JKT41, an oligodeoxynucleotide corresponding to the cis-acting element in intron 9 of the MPO gene. Recombinant HNRPDL also interacted with poly(G) and poly(A), but not with poly(U) or poly(C). Transient expression of HNRPDL repressed expression of reporter genes located downstream of the intron 9 element of JKT41 or the intron 7 element of FERE27, another oligodeoxynucleotide corresponding to MPO.
Kamei et al. (1999) determined that the HNRNPDL gene contains 9 exons and spans approximately 5.6 kb. The 5-prime flanking region shows 66% CG content and 8 SP1 (189906)-binding sites, but no CAAT or TATA boxes.
By FISH, Kamei et al. (1999) mapped the HNRNPDL gene to chromosome 4q13-q21.
Gross (2014) mapped the HNRNPDL gene to chromosome 4q21.22 based on an alignment of the HNRNPDL sequence (GenBank BC011714) with the genomic sequence (GRCh38).
In affected members of a Brazilian family and a Uruguayan family with autosomal dominant limb-girdle muscular dystrophy-3 (LGMDD3; 609115), earlier symbolized LGMD1G, Vieira et al. (2014) identified different heterozygous missense mutations affecting the same codon in the HNRNPDL gene (D378N, 607137.0001 and D378H, 607137.0002, respectively). The mutations were found using a combination of linkage analysis and whole-genome sequencing. Functional studies of the variants were not performed. Loss of the yeast homolog hrp1 had pronounced effects on both protein levels and cell localizations, demonstrating that its loss was detrimental to cell physiology. The loss of Hrp1 on the yeast proteome revealed dramatic reorganization of proteins involved in RNA-processing pathways. Skeletal muscle biopsy from a Brazilian patient with severe disease showed a clear myopathic pattern with necrotic fibers and rimmed vacuoles, as well as some neurogenic involvement, as evidenced by small angulated fibers, predominance of type II fibers, and fiber-type grouping. Immunohistochemical studies showed higher variability in nuclear labeling of HNRNPDL compared to controls, with some nuclei showing a strong condensed signal and others showing a diffuse pattern around the nucleus.
Vieira et al. (2014) found that morpholino knockdown of hnrpdl in zebrafish resulted in body shape defects and twisted tails, as well as restricted movement and uncoordination, consistent with a myopathy. Myofibers isolated from mutant zebrafish were disorganized.
In affected members of a large Brazilian kindred with autosomal dominant limb-girdle muscular dystrophy type 1G (LGMDD3; 609115), originally reported by Starling et al. (2004), Vieira et al. (2014) identified a heterozygous c.1667G-A transition in exon 6 of the HNRNPDL gene, resulting in an asp378-to-asn (D378N) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and was not present in 604 Brazilian controls. A mutation at the same residue (D378H; 607137.0002) was found in another family with the disorder. Functional studies of the variants were not performed.
In affected members of a large Uruguayan family with autosomal dominant limb-girdle muscular dystrophy type 1G (LGMDD3; 609115), Vieira et al. (2014) identified a heterozygous c.1667G-C transversion in exon 6 of the HNRNPDL gene, resulting in an asp378-to-his (D378H) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and was not present in 604 Brazilian controls. A mutation at the same residue (D378N; 607137.0001) was found in another family with the disorder. Functional studies of the variants were not performed.
Doi, A., Shiosaka, T., Takaoka, Y., Yanagisawa, K., Fujita, S. Molecular cloning of the cDNA encoding A+U-rich element RNA binding factor. Biochim. Biophys. Acta 1396: 51-56, 1998. [PubMed: 9524220] [Full Text: https://doi.org/10.1016/s0167-4781(97)00223-6]
Gross, M. B. Personal Communication. Baltimore, Md. 8/29/2014.
Kamei, D., Tsuchiya, N., Yamazaki, M., Meguro, H., Yamada, M. Two forms of expression and genomic structure of the human heterogeneous nuclear ribonucleoprotein D-like JKTBP gene (HNRPDL). Gene 228: 13-22, 1999. [PubMed: 10072754] [Full Text: https://doi.org/10.1016/s0378-1119(99)00020-7]
Starling, A., Kok, F., Passos-Bueno, M. R., Vainzof, M., Zatz, M. A new form of autosomal dominant limb-girdle muscular dystrophy (LGMD1G) with progressive fingers and toes flexion limitation maps to chromosome 4p21. Europ. J. Hum. Genet. 12: 1033-1040, 2004. Note: Erratum: Europ. J. Hum. Genet. 13: 264 only, 2005. [PubMed: 15367920] [Full Text: https://doi.org/10.1038/sj.ejhg.5201289]
Tsuchiya, N., Kamei, D., Takano, A., Matsui, T., Yamada, M. Cloning and characterization of a cDNA encoding a novel heterogeneous nuclear ribonucleoprotein-like protein and its expression in myeloid leukemia cells. J. Biochem. 123: 499-507, 1998. [PubMed: 9538234] [Full Text: https://doi.org/10.1093/oxfordjournals.jbchem.a021964]
Vieira, N. M., Naslavsky, M. S., Licinio, L., Kok, F., Schlesinger, D., Vainzof, M., Sanchez, N., Kitajima, J. P., Gal, L., Cavacana, N., Serafini, P. R., Chuartzman, S., Vasquez, C., Mimbacas, A., Nigro, V., Pavanello, R. C., Schuldiner, M., Kunkel, L. M., Zatz, M. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum. Molec. Genet. 23: 4103-4110, 2014. [PubMed: 24647604] [Full Text: https://doi.org/10.1093/hmg/ddu127]