Alternative titles; symbols
HGNC Approved Gene Symbol: PLPBP
Cytogenetic location: 8p11.23 Genomic coordinates (GRCh38) : 8:37,762,546-37,779,768 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p11.23 | Epilepsy, early-onset, 1, vitamin B6-dependent | 617290 | Autosomal recessive | 3 |
The PROSC gene encodes a ubiquitously expressed cytoplasmic protein with a pyridoxal 5-prime phosphate (PLP)-binding barrel domain that likely plays a role in intracellular homeostatic regulation of PLP (summary by Darin et al., 2016).
By sequencing a 1.8-Mb segment of human 8p11.2, coupled with bioinformatics analyses, Ikegawa et al. (1999) identified a novel gene. Since the P. aeruginosa homolog of this novel gene is located upstream of and may be cotranscribed with a known proline biosynthetic gene, the authors called the human gene PROSC, for 'proline synthetase cotranscribed, bacterial homolog.' Northern blot analysis detected a 2.6-kb PROSC transcript that was expressed in all human adult and fetal tissues tested. Ikegawa et al. (1999) isolated cDNAs corresponding to the full-length PROSC transcript. The deduced 275-amino acid PROSC protein shares 86.5% sequence identity with mouse Prosc and 28% identity with its P. aeruginosa homolog. PROSC is predicted to be a soluble, cytoplasmic protein. It contains a putative N-linked glycosylation site and a putative cAMP- and cGMP-dependent protein kinase phosphorylation site.
Ikegawa et al. (1999) determined that the PROSC gene spans 17.2 kb and contains 8 exons. It is oriented in a 5-prime to 3-prime direction from telomere to centromere.
Ikegawa et al. (1999) mapped the PROSC gene between the proximal STS marker NIB1979 and the distal STS marker AFMA295ZD5 on chromosome 8p11.2.
In 7 patients from 5 unrelated families with early-onset vitamin B6-dependent epilepsy (EPEO1; 617290), Darin et al. (2016) identified homozygous or compound heterozygous mutations in the PROSC gene (see, e.g., 604436.0001-604436.0006). The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing. Mutations in the 4 other patients were found by Sanger sequencing of the PROSC gene in 29 children with B6-responsive epilepsy. Patient plasma pyridoxal 5-prime phosphate levels in those receiving B6 treatment were increased compared to controls, and PLP levels in cultured patient fibroblasts were also increased. Complementation studies in PROSC-deficient E. coli showed that several of the mutations could not restore growth, indicating a loss-of-function effect. Darin et al. (2016) noted that PLP is a highly reactive aldehyde and may interact nonspecifically with intracellular proteins and small molecules, resulting in a toxic effect. The genetic findings were consistent with a defect in intracellular homeostatic regulation of PLP.
In 3 affected members of a consanguineous Syrian family with early-onset vitamin B6-dependent epilepsy (EPEO1; 617290), Darin et al. (2016) identified a homozygous c.233C-G transversion (c.233C-G, NM_007198.3) in exon 3 of the PROSC gene, resulting in a ser78-to-ter (S78X) substitution. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or ExAC databases, but was found in heterozygous state in 1 of 237 Swedish and 89 Syrian control individuals living in Sweden. Western blot analysis of patient cells showed no detectable PROSC, and complementation studies in PROSC-deficient E. coli showed that the S78X mutation could not restore growth, indicating a loss-of-function effect.
In a 3.5-year-old girl (patient 4), born of consanguineous Indian parents, with early-onset vitamin B6-dependent epilepsy (EPEO1; 617290), Darin et al. (2016) identified a homozygous c.524T-C transition (c.524T-C, NM_007198.3) in exon 6 of the PROSC gene, resulting in a leu175-to-pro (L175P) substitution at a highly conserved residue. The variant was found at a low frequency (1 in 121,412 alleles) in the ExAC database. Western blot analysis of patient cells showed no detectable PROSC, and complementation studies in PROSC-deficient E. coli showed that the L175P mutation could not restore growth, indicating a loss-of-function effect.
In a 5.5-year-old German girl (patient 5) with early-onset vitamin B6-dependent epilepsy (EPEO1; 617290), Darin et al. (2016) identified compound heterozygous splice site mutations in the PROSC gene: a G-to-A transition in intron 2 (c.207+1G-A), and an A-to-G transition in intron 4 (c.320-2A-G; 604436.0004). The mutations, which were found by Sanger sequencing, segregated with the disorder in the family. The c.207+1G-A variant was found at a low frequency (4 in 121,408 alleles) in the ExAC database; the c.320-2A-G variant was not found in the ExAC database. Analysis of patient cells showed that the mutations resulted in abnormal splicing with several variant transcripts, including Val70IlefsTer6, Asp34_Tyr69del, and Ala107_Thr116del. Western blot analysis of patient cells showed no detectable PROSC.
For discussion of the A-to-G transition in intron 4 (c.320-2A-G) of the PROSC gene that was found in compound heterozygous state in a patient with early-onset vitamin B6-dependent epilepsy (EPEO1; 617290) by Darin et al. (2016), see 604436.0003.
In a 16-year-old Italian boy (patient 7) with early-onset vitamin B6-dependent epilepsy (EPEO1; 617290), Darin et al. (2016) identified compound heterozygous missense mutations in the PROSC gene: a c.260C-T transition (c.260C-T, NM_007198.3) in exon 4, resulting in a pro87-to-leu (P87L) substitution at a residue conserved across higher organisms, and a c.722G-A transition in exon 8, resulting in an arg241-to-gln (R241Q; 604436.0006) substitution at a highly conserved residue. The mutations, which were found by Sanger sequencing, segregated with the disorder in the family. Both variants were found at low frequencies in the ExAC database (P87L in 2 of 121,410 alleles, and R241Q in 5 of 121,407 alleles). Complementation studies in PROSC-deficient E. coli showed that the R241Q mutation could not restore growth, indicating a loss-of-function effect, whereas the P87L mutation was able to restore growth, suggesting that the mutant protein retained some function.
For discussion of the c.722G-A transition (c.722G-A, NM_007198.3) in exon 8 of the PROSC gene, resulting in an arg241-to-gln (R241Q) substitution, that was found in compound heterozygous state in a patient with early-onset vitamin B6-dependent epilepsy (EPEO1; 617290) by Darin et al. (2016), see 604436.0005.
Darin, N., Reid, E., Prunetti, L., Samuelsson, L., Husain, R. A., Wilson, M., El Yacoubi, B., Footitt, E., Chong, W. K., Wilson, L. C., Prunty, H., Pope, S., Heales, S., Lascelles, L., Champion, M., Wassmer, E., Veggiotti, P., de Crecy-Lagard, V., Mills, P. B., Clayton, P. T. Mutations in PROSC disrupt cellular pyridoxal phosphate homeostasis and cause vitamin-B6-dependent epilepsy. Am. J. Hum. Genet. 99: 1325-1337, 2016. [PubMed: 27912044] [Full Text: https://doi.org/10.1016/j.ajhg.2016.10.011]
Ikegawa, S., Isomura, M., Koshizuka, Y., Nakamura, Y. Cloning and characterization of human and mouse PROSC (proline synthetase co-transcribed) genes. J. Hum. Genet. 44: 337-342, 1999. [PubMed: 10496079] [Full Text: https://doi.org/10.1007/s100380050172]