Alternative titles; symbols
HGNC Approved Gene Symbol: HOGA1
SNOMEDCT: 734990008;
Cytogenetic location: 10q24.2 Genomic coordinates (GRCh38) : 10:97,584,389-97,612,802 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q24.2 | Hyperoxaluria, primary, type III | 613616 | Autosomal recessive | 3 |
By searching for genes in a region of chromosome 10 linked to primary hyperoxaluria type III (HP3; 613616), followed by PCR of genomic DNA, Belostotsky et al. (2010) cloned DHDPSL. They noted that, despite the designation 'mitochondrial dihydrodipicolinate synthase-like,' DHDPSL shares little homology with E. coli dihydrodipicolinate synthase (Dhdps), particularly in the putative substrate-binding region. Moreover, neither lysine biosynthesis nor sialic acid metabolism, for which Dhdps is responsible, occurs in vertebrate mitochondria. Instead, Belostotsky et al. (2010) speculated that DHDPSL encodes mitochondrial 4-hydroxy-2-oxoglutarate aldolase (EC 4.1.3.16), which catalyzes the final step in the metabolic pathway of hydroxyproline, releasing the products glyoxylate and pyruvate. Belostotsky et al. (2010) stated that DHDPSL is predominantly expressed in liver and kidney.
Hartz (2010) mapped the DHDPSL gene to chromosome 10q24.2 based on an alignment of the DHDPSL sequence (GenBank BC011916) with the genomic sequence (GRCh37).
In 15 patients from 9 unrelated families with primary hyperoxaluria mapping to chromosome 10 (HP3; 613616), in whom mutations in the AGXT (604285) and GRHPR (604296) had been excluded, Belostotsky et al. (2010) analyzed the candidate gene DHDPSL and identified homozygosity or compound heterozygosity for 6 different mutations (613597.0001-613597.0006). The unaffected parents were all heterozygous for 1 of the mutations.
In a 27-month-old Chinese boy with primary hyperoxaluria in whom mutations in the AGXT (604285) and GRHPR (604296) genes had been excluded, Wang et al. (2015) identified compound heterozygous mutations in the HOGA1 gene (613597.0007 and 613597.0008). The mutations segregated with the phenotype in the family.
In 3 unrelated boys, born to consanguineous Tunisian parents, with primary hyperoxaluria, who did not have mutations in the AGXT or GRHPR gene, M'dimegh et al. (2017) identified mutations in the HOGA1 gene: 2 boys were homozygous for a P190L and a G287V mutation (613597.0002), respectively, and the other boy was heterozygous for the G287V mutation.
In affected members of 4 unrelated Ashkenazi Jewish families with calcium oxalate nephrolithiasis (HP3; 613616), Belostotsky et al. (2010) identified homozygosity for a 3-bp deletion (944delAGG) in exon 7 of the DHDPSL gene, resulting in deletion of glu315 (glu315del). The unaffected parents were all heterozygous for the deletion, which was not found in 216 chromosomes from healthy unrelated Ashkenazi Jewish individuals or in 226 chromosomes from European American individuals. The glu315del mutation was detected in compound heterozygosity with another DHDPSL mutation in affected members from 3 additional HP3 families (see 613597.0002-613597.0004, respectively).
In 5 affected members of an Ashkenazi Jewish family with primary hyperoxaluria (HP3; 613616), Belostotsky et al. (2010) identified compound heterozygosity for an 860G-T transversion in the DHDPSL gene, resulting in a gly287-to-val (G287V) substitution, and glu315del (613597.0001). The unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 216 chromosomes from healthy unrelated Ashkenazi Jewish individuals or in 226 chromosomes from European American individuals.
In 2 affected members of a European American family with calcium oxalate nephrolithiasis (HP3; 613616), Belostotsky et al. (2010) identified compound heterozygosity for a 289C-T transition in the DHDPSL gene, resulting in an arg97-to-cys (R97C) substitution, and glu315del (613597.0001). The unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 226 chromosomes from European American individuals.
In a 24-year-old woman from a European American family with calcium oxalate nephrolithiasis (HP3; 613616), Belostotsky et al. (2010) identified compound heterozygosity for an intronic G-to-T transversion (701+4G-T) in the DHDPSL gene, predicted to result in insertion of 17 amino acid residues, and glu315del (613597.0001). The unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 226 chromosomes from European American individuals.
In a 15-year-old boy from a European American family with calcium oxalate nephrolithiasis (HP3; 613616), Belostotsky et al. (2010) identified compound heterozygosity for a 209G-C transversion in the DHDPSL gene, resulting in an arg70-to-pro (R70P) substitution, and the 704+4G-T splice site mutation (613597.0004). The unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 226 chromosomes from European American individuals.
In a 12-year-old boy from a European American family with calcium oxalate nephrolithiasis (HP3; 613616), Belostotsky et al. (2010) identified homozygosity for a 769T-G transversion in the DHDPSL gene, resulting in a cys257-to-gly (C257G) substitution. The unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 226 chromosomes from European American individuals. His brother, who had only transient hyperoxaluria and had never formed a kidney stone, did not carry the mutation.
In a 27-month-old Chinese boy with primary hyperoxaluria type III (HP3; 613616), Wang et al. (2015) identified compound heterozygous mutations in the HOGA1 gene: a 2-bp substitution at the last nucleotide of exon 6 (c.834_834+1GG-TT) and a c.834G-A transition (613597.0008) at the last nucleotide of exon 6. A minigene assay based on the pSPL3 exon trapping vector suggested that both of these mutations affected splicing. The first one resulted in complete skipping of exon 6, resulting in a frameshift from codon 235 and premature termination at position 268 in exon 7. The second led to expression of 2 transcripts of which the majority were missing exon 6. The first mutation was inherited from his mother, and the second was inherited from his father. Direct sequencing failed to identify these mutations in 100 unrelated healthy subjects.
For discussion of the c.834G-A transition in the HOGA1 gene that was found in compound heterozygous state in a Chinese boy with primary hyperoxaluria type III (HP3; 613616) by Wang et al. (2015), see 613597.0007.
Belostotsky, R., Seboun, E., Idelson, G. H., Milliner, D. S., Becker-Cohen, R., Rinat, C., Monico, C. G., Feinstein, S., Ben-Shalom, E., Magen, D., Weissman, I., Charon, C., Frishberg, Y. Mutations in DHDPSL are responsible for primary hyperoxaluria type III. Am. J. Hum. Genet. 87: 392-399, 2010. [PubMed: 20797690] [Full Text: https://doi.org/10.1016/j.ajhg.2010.07.023]
Hartz, P. A. Personal Communication. Baltimore, Md. 10/12/2010.
M'dimegh, S., Aquaviva-bourdain, C., Omezzine, A., Souche, G., M'barek, I., Abidi, K., Gargah, T., Abroug, S., Bouslama, A. HOGA1 gene mutations of primary hyperoxaluria type 3 in Tunisian patients. J. Clin. Lab. Anal. 31: e22053, 2017. Note: Electronic Article. [PubMed: 27561601] [Full Text: https://doi.org/10.1002/jcla.22053]
Wang, X., Zhao, X., Wang, X., Yao, J., Zhang, F., Lang, Y., Tuffery-Giraud, S., Bottillo, I., Shao, L. Two novel HOGA1 splicing mutations identified in a Chinese patient with primary hyperoxaluria type 3. Am. J. Nephrol. 42: 78-84, 2015. [PubMed: 26340091] [Full Text: https://doi.org/10.1159/000439232]