Alternative titles; symbols
HGNC Approved Gene Symbol: GPD1L
Cytogenetic location: 3p22.3 Genomic coordinates (GRCh38) : 3:32,106,620-32,168,709 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p22.3 | Brugada syndrome 2 | 611777 | Autosomal dominant | 3 |
By sequencing clones obtained from a myeloid leukemia cell line cDNA library, Nagase et al. (1995) cloned GPD1L, which they designated KIAA0089. The deduced 411-amino acid protein contains an NAD-dependent glycerol-3-phosphate dehydrogenase (GPD1; 138420) motif, and it shares 71.8% identity with GPD1. Northern blot analysis detected a single GPD1L transcript in all tissues examined except liver. Highest expression was in heart and skeletal muscle.
London et al. (2007) determined that the deduced 351-amino acid GPD1L protein contains an N-terminal NAD+ consensus binding site, followed by a site homologous to the cardiac sodium channel SCN5A (600163), and a C-terminal lys206 residue. Northern blot analysis detected highest expression of an approximately 4-kb transcript in heart, with lower levels in skeletal muscle, kidney, lung, and other organs. Western blot analysis of mouse, rabbit, and human heart lysates detected the protein at an apparent molecular mass of about 40 kD, with concentration in membrane fractions.
London et al. (2007) determined that the GPD1L gene contains 8 exons and spans 62.2 kb.
By PCR of human-rodent hybrid cell lines, Nagase et al. (1995), mapped the GPD1L gene to chromosome 3. By linkage with Brugada syndrome-2 (BRGDA2; 611777) and by database analysis, London et al. (2007) mapped the GPD1L gene to chromosome 3p24-p22.
In a large family with Brugada syndrome-2 (611777), previously studied by Weiss et al. (2002) with linkage analysis that excluded the SCN5A gene (600163), London et al. (2007) performed fine mapping and narrowed the critical region to approximately 1,000 kb on chromosome 3p24. Candidate genes in the area were analyzed by SSCP and direct sequencing, and a mutation in the GPD1L gene (A280V; 611778.0001) was identified in 16 phenotypically affected individuals and 27 others (37% penetrance). The mutation was not found in more than 1,000 reference alleles; no mutations in the GPD1L gene were identified in the probands of 19 smaller families with Brugada syndrome. Studies in HEK cells demonstrated that the A280V mutation reduced the inward sodium current by about 50% and decreased SCN5A surface expression by about 30%.
Van Norstrand et al. (2007) analyzed the GPD1L gene in necropsy tissue from 83 unrelated cases of sudden unexplained death (see SIDS; 272120) and identified a mutation (E83K; 611778.0002) in a boy who died at 3 months of age. Mutation analysis was then performed on genomic DNA derived from 221 cases of SIDS, revealing 2 additional mutations, in a girl who died at 5 weeks (I124K; 611778.0003) and a boy who died at 1 month of age (R273C; 611778.0004), respectively. They found that cotransfection of wildtype GPD1L with SCN5A into human embryonic kidney cells or mouse neonatal cardiomyocytes resulted in robust SCN5A-dependent sodium current density. However, GPD1L containing the E83K, I124V, R273C mutations reduced peak SCN5A-dependent sodium current density. The mutations did not affect the kinetics of channel activation or inactivation.
In a large multigenerational family with Brugada syndrome-2 (611777), previously studied by Weiss et al. (2002), London et al. (2007) identified heterozygosity for an 899C-T transition in exon 6 of the GPD1L gene, resulting in an ala280-to-val (A280V) substitution. The mutation was found in all 16 phenotypically affected individuals and 27 others (37% penetrance); it was not found in more than 1,000 reference alleles. Studies in HEK cells demonstrated that A280V reduced the inward sodium current by about 50% and decreased SCN5A surface expression by about 30%, but did not affect the kinetics of channel activation or deactivation; these effects were specific to the cardiac sodium channel.
In a 3-month-old white boy who died of SIDS (272120; see also Brugada syndrome-2, 611777), Van Norstrand et al. (2007) identified a 307G-A transition in the GPD1L gene, resulting in a glu83-to-lys (E83K) substitution at a highly conserved residue in the N-terminal NAD binding domain. The E83K mutation, which significantly reduced the sodium current in HEK cells and neonatal mouse cardiomyocytes, was not found in 600 reference alleles. The child had a family history of poorly documented cardiac arrhythmias, but his parents declined participation.
In a 5-week-old white girl who died of SIDS (272120; see also Brugada syndrome-2, 611777), Van Norstrand et al. (2007) identified a 430A-G transition in the GPD1L gene, resulting in an ile124-to-val (I124V) substitution at a highly conserved residue in the N-terminal NAD binding domain. The I124V mutation, which significantly reduced the sodium current in HEK cells and neonatal mouse cardiomyocytes, was not found in 600 reference alleles.
In a 1-month-old white boy who died of SIDS (272120; see also Brugada syndrome-2, 611777), Van Norstrand et al. (2007) identified an 877C-T transition in the GPD1L gene, resulting in an arg273-to-cys (R273C) substitution at a highly conserved residue in the C-terminal substrate-binding domain. The R273C mutation, which significantly reduced the sodium current in HEK cells and neonatal mouse cardiomyocytes, was not found in 600 reference alleles.
London, B., Michalec, M., Mehdi, H., Zhu, X., Kerchner, L., Sanyal, S., Viswanathan, P. C., Pfahnl, A. E., Shang, L. L., Madhusudanan, M., Baty, C. J., Lagana, S., Aleong, R., Gutmann, R., Ackerman, M. J., McNamara, D. M., Weiss, R., Dudley, S. C., Jr. Mutation in glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias. Circulation 116: 2260-2268, 2007. [PubMed: 17967977] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.703330]
Nagase, T, Miyajima, N, Tanaka, A., Sazuka, T., Seki, N., Sato, S., Tabata, S., Ishikawa, K., Kawarabayashi, Y., Kotani, H., Nomura, N. Prediction of the coding sequences of unidentified human genes. III. The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 37-43, 1995. [PubMed: 7788527] [Full Text: https://doi.org/10.1093/dnares/2.1.37]
Van Norstrand, D. W., Valdivia, C. R., Tester, D. J., Ueda, K., London, B., Makielski, J. C., Ackerman, M. J. Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) mutations in sudden infant death syndrome. Circulation 116: 2253-2259, 2007. [PubMed: 17967976] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.107.704627]
Weiss, R., Barmada, M. M., Nguyen, T., Seibel, J. S., Cavlovich, D., Kornblit, C. A., Angelilli, A., Villanueva, F., McNamara, D. M., London, B. Clinical and molecular heterogeneity in the Brugada syndrome: a novel gene locus on chromosome 3. Circulation 105: 707-713, 2002. [PubMed: 11839626] [Full Text: https://doi.org/10.1161/hc0602.103618]