Alternative titles; symbols
HGNC Approved Gene Symbol: RSPRY1
SNOMEDCT: 1187303004;
Cytogenetic location: 16q13 Genomic coordinates (GRCh38): 16:57,186,152-57,240,469 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q13 | Spondyloepimetaphyseal dysplasia, Faden-Alkuraya type | 616723 | Autosomal recessive | 3 |
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2001) cloned RSPRY1, which they designated KIAA1972. The deduced 576-amino acid protein has a SPRY domain and a putative C3HC4-type zinc finger domain, suggesting the protein has a function in nucleic acid management. RT-PCR ELISA detected highest KIAA1972 expression in liver, kidney, testis, ovary, and spleen, with moderate expression in spinal cord and fetal liver, and lower expression in all other tissues examined, including adult and fetal brain. Within specific adult brain regions, highest expression was detected in substantia nigra.
Faden et al. (2015) examined the expression of Rspry1 transcripts and localization of the encoded protein by in situ hybridization, RT-PCR, and immunohistochemistry in mid- to late-gestation mouse embryos and newborns. Rspry1 transcripts and encoded protein were expressed in and localized to intact mouse limb bud mesenchyme from as early as embryonic day (E) 12.5. At E18.5, coinciding with primary ossification in the mouse, Rspry1 protein was abundantly detected in most developing endochondral bones and in skeletal muscles, as well as in developing heart, kidney, and brain. In the E18.5 forelimb, Rspry1 was detected in the humerus, ulna, radius, carpals, and metacarpals. Rspry1 was also detected in the bones of the E18.5 hindlimb, including the femur, tibia, fibula, tarsals, and metatarsals. Strong localization was detected in both osteoblasts and osteocytes within these bones, with minimal localization in chondrocytes. A second site of prominent Rspry1 bone localization was in the perichondrium and periosteum, with highest levels in the innermost cellular layer. Expression was also detected in embryonic and postnatal brain and in developing craniofacial tissues.
Waddell et al. (2016) cloned mouse Rspry1 from C2C12 mouse myoblast cells. The deduced 576-amino acid protein has a calculated molecular mass of 64 kD. At its C-terminal end, Rspry1 contains a SPRY domain followed by a C3HC4-type RING finger domain. The human RSPRY1 protein shares 97% amino acid identity with mouse and rat Rspry1 and has a similar structure. Western blot analysis detected Rspry1 protein in differentiating C2C12 mouse cells. Fluorescence-tagged Rspry1 localized to cytoplasm in transfected C2C12 cells.
Waddell et al. (2016) determined that the mouse Rspry1 gene contains 14 coding exons and 1 noncoding exon. The 5-prime flanking region of the Rspry1 gene shares a 230-bp regulatory region with the Fam192a gene (617766), and this regulatory region is conserved in rat and human. Genomic sequence analysis of the mouse, rat, and human regulatory regions revealed a putative E-box sequence, 2 putative AP2 (see 107580) consensus sequences, a putative CCAAT box, and 2 putative GC boxes.
Hartz (2015) mapped the RSPRY1 gene to chromosome 16q13 based on an alignment of the RSPRY1 sequence (GenBank AB075852) with the genomic sequence (GRCh38).
Waddell et al. (2016) mapped the Rspry1 gene to mouse chromosome 8. It is transcribed in the opposite orientation to the Fam192a gene, with which it shares a 5-prime regulatory region, and this arrangement is conserved in human.
Using microarray analysis, Waddell et al. (2016) found modestly increased expression of Rspry1 in mouse muscle tissue during denervation-induced skeletal muscle atrophy. A 529-bp fragment of the proximal regulatory region of Rspry1 drove reporter gene expression in C2C12 mouse myoblast cells. Mutation of the E-box in the Rspry1 regulatory region significantly decreased expression of a reporter gene in C2C12 cells, whereas overexpression of Myod1 (159970) increased expression of the reporter gene in C2C12 cells and HEK293T cells.
In affected members of a consanguineous Bedouin Saudi family with spondyloepimetaphyseal dysplasia of the Faden-Alkuraya type (SEMDFA; 616723), Faden et al. (2015) identified homozygosity for a 1-bp duplication in the RSPRY1 gene (616585.0001). Using a gene-centric 'matchmaking' system, Faden et al. (2015) identified a similarly affected Peruvian boy who was homozygous for a missense mutation in RSPRY1 (G41C; 616585.0002).
In affected members of a consanguineous Bedouin Saudi family with spondyloepimetaphyseal dysplasia of the Faden-Alkuraya type (SEMDFA; 616723), Faden et al. (2015) identified homozygosity for a 1-bp duplication (c.1279dupA, NM_133368.1) in the RSPRY1 gene, causing a frameshift predicted to result in premature termination (Thr427AsnfsTer10). The mutation segregated with disease in the family and was not found in 650 Saudi control exomes or in the ExAC database. RT-PCR revealed significant reduction of RSPRY1 transcript in patient blood compared to controls.
In an 8-year-old Peruvian boy with spondyloepimetaphyseal dysplasia of the Faden-Alkuraya type (SEMDFA; 616723), Faden et al. (2015) identified homozygosity for a c.121G-T transversion (c.121G-T, NM_133368.1) in the RSPRY1 gene, resulting in a gly41-to-cys (G41C) substitution at a conserved residue. His parents, who came from a small isolated region of Peru, were both heterozygous for the mutation, which was not found in an in-house exome database or in the dbSNP, 1000 Genomes Project, NHLBI Exome Project, or ExAC databases.
Faden, M., AlZahrani, F., Mendoza-Londono, R., Dupuis, L., Hartley, T., Kannu, P., Raiman, J. A., Howard, A., Qin, W., Tetreault, M., Xi, J. Q., Al-Thamer, I., Care4Rare Canada Consortium, Maas, R. L., Boycott, K., Alkuraya, F. S. Identification of a recognizable progressive skeletal dysplasia caused by RSPRY1 mutations. Am. J. Hum. Genet. 97: 608-615, 2015. [PubMed: 26365341] [Full Text: https://doi.org/10.1016/j.ajhg.2015.08.007]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/2/2015.
Nagase, T., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XXII. The complete sequences of 50 new cDNA clones which code for large proteins. DNA Res. 8: 319-327, 2001. [PubMed: 11853319] [Full Text: https://doi.org/10.1093/dnares/8.6.319]
Waddell, D. S., Duffin, P. J., Haddock, A. N., Triplett, V. E., Saredy, J. J., Kakareka, K. M., Eldredge, J. T. Isolation, expression analysis and characterization of NEFA-interacting nuclear protein 30 and RNG finger and SPRY domain containing 1 in skeletal muscle. Gene 576: 319-332, 2016. [PubMed: 26497270] [Full Text: https://doi.org/10.1016/j.gene.2015.10.046]