Alternative titles; symbols
HGNC Approved Gene Symbol: PEPD
SNOMEDCT: 360994007, 410055005;
Cytogenetic location: 19q13.11 Genomic coordinates (GRCh38) : 19:33,386,950-33,521,791 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.11 | Prolidase deficiency | 170100 | Autosomal recessive | 3 |
Peptidase D (EC 3.4.13.9), also known as prolidase, imidodipeptidase, proline dipeptidase, and aminoacyl-L-proline hydrolase, specifically splits iminodipeptides with C-terminal proline or hydroxyproline. The enzyme prolinase (EC 3.4.13.8) splits iminodipeptides with N-terminal proline or hydroxyproline. The 2 dipeptidases play an important role in collagen metabolism because of the high level of iminoacids in collagen (proline and hydroxyproline constitute 25%) (Royce and Steinmann, 2002) and seem to be important for protein catabolism in general (Lupi et al., 2008).
Endo et al. (1989) isolated prolidase cDNA clones from human liver and placenta cDNA libraries. The deduced mature enzyme contains 492 amino acids with a calculated molecular mass of 54.3 kD. Northern blot analysis detected a single mRNA of approximately 2.1 kb.
Tanoue et al. (1990) demonstrated that the prolidase gene contains 15 exons and spans more than 130 kb. All of the splice donor and acceptor sites conform to the GT/AG rule. By nuclease S1 mapping and primer extension, they determined that the transcription initiation site is located 131 bases upstream from the initiation codon. A 'CAAT' box-like sequence was found 67 bases from the cap site, but there was no 'TATA' box-like sequence. There were 7 sets of sequences resembling the transcription factor Sp1 binding sites.
Peptidase D was assigned to chromosome 19 by McAlpine et al. (1976) and by Brown et al. (1978). Eiberg et al. (1983) showed that PEPD is probably linked to the C3-LE-DM-SE-LU linkage group, thus corroborating the assignment of this large group to chromosome 19. They found a lod score (male and female) for PEPD-Se of 2.14 at theta 0.05; a previous score of 0.94 at theta 0.20 was reported in other families. PEPD-C3 (male) gave positive scores. GPI and PEPD, which are on chromosome 19 in man, are on chromosome 9 of the Chinese hamster, and TPI, which is on chromosome 12 of man, is on Chinese hamster chromosome 8 (Siciliano et al., 1983). Linkage of peptidase D to myotonic dystrophy (O'Brien et al., 1983) proves the assignment of the Lutheran-secretor linkage group to chromosome 19 and provides regional assignment to 19pter-q13. Brook et al. (1985) gave a regionalization of 19p13.2-q13.2. Ball et al. (1985) found close linkage between PEPD and APOC2 (608083). Lusis et al. (1986) used a reciprocal whole arm translocation between the long arm of chromosome 19 and the short arm of chromosome 1 to determine that the APOC1, APOC2, APOE and GPI loci are on the long arm and the LDLR, C3 and PEPD loci on the short arm. They isolated a single lambda phage carrying APOC1 and part of APOE. These genes are 6 kb apart and arranged tandemly. APOC2 and APOE were previously shown to be tightly linked. Friedrich et al. (1987) cited evidence from somatic cell hybrid studies using cells with various chromosome 19 rearrangements that the PEPD locus is unequivocally on the long arm of chromosome 19. Thus, PEPD is located at 19cen-q13.11. Using a panel of human-rodent somatic cell hybrids containing different regions of chromosome 19, Davis et al. (1987) also assigned PEPD to the long arm of chromosome 19.
Hartz (2010) mapped the PEPD gene to chromosome 19q13.11 based on an alignment of the PEPD sequence (GenBank BT006692) with the genomic sequence (GRCh37).
Prolidase is involved in the final stage of degradation of endogenous and dietary proteins, in particular in collagen catabolism (Cunningham and O'Connor, 1997).
Lewis and Harris (1969) identified a number of electrophoretic variants of peptidase D of red cells.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
In 2 unrelated patients with prolidase deficiency (170100), Tanoue et al. (1990) identified homozygosity for a mutation in the PEPD gene (613230.0001).
Wang et al. (2006) reported 4 Geauga Amish children with prolidase deficiency, born of consanguineous parents whose ancestry could be traced to common ascendants 7 or 8 generations back, in whom they identified a homozygous nonsense mutation in the PEPD gene (613230.0008).
Falik-Zaccai et al. (2010) identified the same PEPD mutation (S202F; 613230.0011) in 17 patients from northern Israel with prolidase deficiency. The patients were from 6 Druze kindreds living in 4 different villages and from 2 Arab Muslim kindreds living in 2 different villages. The separate practices of consanguinity and endogamy reduce the likelihood of genetic interchange between these 2 groups, but haplotype analysis indicated a founder effect. The findings refuted the possibility of the Druze being a homogeneous population, and suggested that the mutation arose before the establishment of the Druze community.
Endo et al. (1989) sequenced a cDNA that codes for the entire mature protein of prolidase. They assigned the gene to 19p13.2 by in situ hybridization.
In 2 unrelated patients with polypeptide-positive (CRM-positive) prolidase deficiency (170100), Tanoue et al. (1990) demonstrated a G-to-A substitution at nucleotide 826 in exon 12 of the PEPD gene, resulting in replacement of aspartic acid by asparagine at amino acid residue 276 (D276N). Both patients were homozygous for this mutation.
Tanoue et al. (1990) analyzed DNA from 3 patients with prolidase deficiency (170100) by Southern blot analysis after TaqI or BamHI digestion. A partial deletion of several hundred basepairs in the PEPD gene, which eliminated exon 14, was found in a patient and her affected sister, who were the offspring of a consanguineous mating (Endo et al., 1990). The defect appeared to be homozygous. No major abnormality in gene structure was found in 2 other patients. Tanoue et al. (1991) gave further details: the 774-bp deletion had termini within short, direct repeats. 'Slipped mispairing' was thought to have been involved in the generation of the deletion. The mutation caused a 192-bp in-frame deletion of prolidase mRNA. The parents were consanguineous. The oldest sister, 25 years of age at the time of report, developed skin lesions at the age of 19 months and required specific treatment. Her homozygous sister had no prominent changes in the skin until age 18 years. Both were negative for immunologic crossreacting material, and there was no residual activity of prolidase in the fibroblasts. Both excreted massive amounts of imidodipeptide in the urine. Erythrocyte prolidase activities were about 50% of the control value in the first-cousin parents.
In an individual with prolidase deficiency (170100) who was asymptomatic at age 11 years, Ledoux et al. (1996) demonstrated compound heterozygosity for a G-to-A transition at nucleotide 551 in exon 8 (R184Q) and a G-to-A transition of nucleotide 833 in exon 123 (G278D; 613230.0004) in the PEPD gene. To assess the biochemical phenotypes of these and 2 previously identified PEPD mutations (G448R, 613230.0005 and E452DEL, 613230.0006), they designed a transient expression system for prolidase in COS-1 cells. The enzyme was expressed as a fusion protein carrying an N-terminal tag, allowing its immunologic discrimination from the endogenous enzyme with a monoclonal antibody. Expression of the R184Q mutation produced 7.4% of control enzymatic activity, whereas the expression of the other 3 mutations produced inactive enzymes. Western analysis of the R184Q, G278D, and G448R prolidases revealed stable immunoreactive material whereas the E452DEL prolidase was not detectable. Pulse-chase metabolic labeling of cells followed by immunoprecipitation revealed that the E452DEL mutant protein was synthesized but had an increased rate of degradation.
For discussion of the gly278-to-asp (G278D) mutation in the PEPD gene that was found in compound heterozygous state in a patient with prolidase deficiency (170100) by Ledoux et al. (1996), see 613230.0003.
In a patient with prolidase deficiency (170100), Ledoux et al. (1994) identified homozygosity for a 1342G-A transition in exon 14 of the PEPD gene, resulting in a gly448-to-arg (G448R) substitution. In another patient with prolidase deficiency, they identified this mutation in heterozygosity; the mutation on the other allele was not yet identified. Also see 613230.0003 and Ledoux et al. (1996).
In 2 brothers with prolidase deficiency, Forlino et al. (2002) identified the G448R mutation in the PEPD gene.
In a patient with prolidase deficiency (170100), Ledoux et al. (1994) identified heterozygosity for a 3-bp deletion in exon 15 of the PEPD gene, resulting in deletion of glutamic acid at residue 452 (E452DEL). The mutation on the other allele was not yet identified. Also see 613230.0003 and Ledoux et al. (1996).
In 2 unrelated Portuguese patients with prolidase deficiency (170100), Lupi et al. (2004) identified a homozygous 3-bp deletion in exon 10 of the PEPD gene, 707delTAC, resulting in deletion of a tyrosine at codon 231 (tyr231).
In 4 Geauga Amish children with prolidase deficiency (170100), born of consanguineous parents and whose ancestry could be traced to common ascendants 7 or 8 generations back, Wang et al. (2006) identified homozygosity for a 793T-C transition in exon 11 of the PEPD gene, resulting in an arg265-to-ter (R265X) substitution. The authors stated that the phenotype in these patients appeared to be more severe than in previously reported patients, and noted that prolidase activity was nearly undetectable in these patients.
In 2 Turkish sisters with prolidase deficiency (170100), Lupi et al. (2006) identified homozygosity for a 1234G-A transition in the PEPD gene, resulting in a glu412-to-lys (E412K) substitution. The 21-year-old proband had eczema-like lesions on the face during childhood; following trauma after puberty, she had recurrent severe leg ulcers. She had no prolidase activity in her erythrocytes or serum. Her 29-year-old sister had no ulcers or any other typical symptoms of prolidase deficiency but had no prolidase activity in her serum or erythrocytes. Their parents were heterozygous for the mutation, which was not found in their healthy brother. Glu412 is a highly conserved residue among different species.
In a Turkish woman with prolidase deficiency (170100), originally described by Pedersen et al. (1983), Lupi et al. (2006) identified a homozygous 13-bp duplication in exon 8 of the PEPD gene, generating a premature stop codon after 18 amino acids from the insertion site and resulting in the absence of prolidase. She had presented in the first year of life with developmental delay, skin ulcers, and failure to thrive. She was diagnosed with prolidase deficiency at age 4 years.
In 17 patients with prolidase deficiency (170100), Falik-Zaccai et al. (2010) identified a homozygous 605C-T transition in exon 8 of the PEPD gene, resulting in a ser202-to-phe (S202F) substitution in a highly conserved residue. All patients with this mutation resided in a small geographic area in northern Israel, and there was a shared haplotype between Druze and Arab Muslims, suggesting a founder effect. There was marked intra- and interfamilial clinical variability, ranging from death in infancy to mild developmental delay or facial dysmorphism.
Ball, S. P., Donald, J. A., Corney, G., Humphries, S. E. Linkage between the loci for peptidase D and apolipoprotein CII on chromosome 19. Ann. Hum. Genet. 49: 129-134, 1985. [PubMed: 3000274] [Full Text: https://doi.org/10.1111/j.1469-1809.1985.tb01684.x]
Brook, J. D., Shaw, D. J., Meredith, A. L., Worwood, M., Cowell, J., Scott, J., Knott, T. J., Litt, M., Bufton, L., Harper, P. S. A somatic cell hybrid panel for chromosome 19: localization of known genes and RFLPs and orientation of the linkage group. (Abstract) Cytogenet. Cell Genet. 40: 590-591, 1985.
Brown, S., Lalley, P. A., Minna, J. D. Assignment of the gene for peptidase S (PEPS) to chromosome 4 in man and confirmation of peptidase D (PEPD) assignment. Cytogenet. Cell Genet. 22: 167-171, 1978. [PubMed: 318156] [Full Text: https://doi.org/10.1159/000130928]
Cunningham, D. F., O'Connor, B. Proline specific peptidases. Biochim. Biophys. Acta 1343: 160-186, 1997. [PubMed: 9434107] [Full Text: https://doi.org/10.1016/s0167-4838(97)00134-9]
Davis, M. B., Schonk, D., Monteiro, M., Oerlemans, F., Povey, S., Wieringa, B. Localization of PEPD to the long arm of chromosome 19. Ann. Hum. Genet. 51: 195-199, 1987. [PubMed: 3479944] [Full Text: https://doi.org/10.1111/j.1469-1809.1987.tb00871.x]
Eiberg, H., Mohr, J., Nielsen, L. S. Indication of linkage between the PEPD locus and the C3-LE-DM-SE-LU linkage group (and support for assignment of this linkage group to chromosome no. 19). (Abstract) Clin. Genet. 23: 228 only, 1983.
Endo, F., Tanoue, A., Kitano, A., Arata, J., Danks, D. M., Lapiere, C. M., Sei, Y., Wadman, S. K., Matsuda, I. Biochemical basis of prolidase deficiency: polypeptide acid RNA phenotypes and the relation to clinical phenotypes. J. Clin. Invest. 85: 162-169, 1990. [PubMed: 1688567] [Full Text: https://doi.org/10.1172/JCI114407]
Endo, F., Tanoue, A., Nakai, H., Hata, A., Indo, Y., Titani, K., Matsuda, I. Primary structure and gene localization of human prolidase. J. Biol. Chem. 264: 4476-4481, 1989. [PubMed: 2925654]
Falik-Zaccai, T. C., Khayat, M., Luder, A., Frenkel, P., Magen, D., Brik, R., Gershoni-Baruch, R., Mandel, H. A broad spectrum of developmental delay in a large cohort of prolidase deficiency patients demonstrates marked interfamilial and intrafamilial phenotypic variability. Am. J. Med. Genet. 153B: 46-56, 2010. [PubMed: 19308961] [Full Text: https://doi.org/10.1002/ajmg.b.30945]
Forlino, A., Lupi, A., Vaghi, P., Cornaglia, A. I., Calligaro, A., Campari, E., Cetta, G. Mutation analysis of five new patients affected by prolidase deficiency: the lack of enzyme activity causes necrosis-like cell death in cultured fibroblasts. Hum. Genet. 111: 314-322, 2002. [PubMed: 12384772] [Full Text: https://doi.org/10.1007/s00439-002-0792-5]
Friedrich, U., Brunner, H., Smeets, D., Lambermon, E., Ropers, H.-H. Three-point linkage analysis employing C3 and 19cen markers assigns the myotonic dystrophy gene to 19q. Hum. Genet. 75: 291-293, 1987. [PubMed: 2881880] [Full Text: https://doi.org/10.1007/BF00281077]
Hartz, P. A. Personal Communication. Baltimore, Md. 1/25/2010.
Ledoux, P., Scriver, C., Hechtman, P. Four novel PEPD alleles causing prolidase deficiency. Am. J. Hum. Genet. 54: 1014-1021, 1994. [PubMed: 8198124]
Ledoux, P., Scriver, C. R., Hechtman, P. Expression and molecular analysis of mutations in prolidase deficiency. Am. J. Hum. Genet. 59: 1035-1039, 1996. [PubMed: 8900231]
Lewis, W. H. P., Harris, H. Peptidase D (prolidase) variants in man. Ann. Hum. Genet. 32: 317-322, 1969. [PubMed: 5822321] [Full Text: https://doi.org/10.1111/j.1469-1809.1969.tb00081.x]
Lupi, A., De Riso, A., Torre, S. D., Rossi, A., Campari, E., Vilarinho, L., Cetta, G., Forlino, A. Characterization of a new PEPD allele causing prolidase deficiency in two unrelated patients: natural-occurrent mutations as a tool to investigate structure-function relationship. J. Hum. Genet. 49: 500-506, 2004. [PubMed: 15309682] [Full Text: https://doi.org/10.1007/s10038-004-0180-1]
Lupi, A., Rossi, A., Campari, E., Pecora, F., Lund, A. M., Elcioglu, N. H., Gultepe, M., Di Rocco, M., Cetta, G., Forlino, A. Molecular characterisation of six patients with prolidase deficiency: identification of the first small duplication in the prolidase gene and of a mutation generating symptomatic and asymptomatic outcomes within the same family. J. Med. Genet. 43: e58, 2006. Note: Electronic Article. [PubMed: 17142620] [Full Text: https://doi.org/10.1136/jmg.2006.043315]
Lupi, A., Tenni, R., Rossi, A., Cetta, G., Forlino, A. Human prolidase and prolidase deficiency: an overview on the characterization of the enzyme involved in proline recycling and on the effects of its mutations. Amino Acids 35: 739-752, 2008. [PubMed: 18340504] [Full Text: https://doi.org/10.1007/s00726-008-0055-4]
Lusis, A. J., Heinzmann, C., Sparkes, R. S., Scott, J., Knott, T. J., Geller, R., Sparkes, M. C., Mohandas, T. Regional mapping of human chromosome 19: organization of genes for plasma lipid transport (APOC1, -C2, and -E and LDLR) and the genes C3, PEPD, and GPI. Proc. Nat. Acad. Sci. 83: 3929-3933, 1986. [PubMed: 3459164] [Full Text: https://doi.org/10.1073/pnas.83.11.3929]
McAlpine, P. J., Mohandas, T., Ray, M., Wang, H., Hamerton, J. L. Assignment of the peptidase D gene locus (PEPD) to chromosome 19 in man. Cytogenet. Cell Genet. 16: 204-205, 1976. [PubMed: 975880] [Full Text: https://doi.org/10.1159/000130591]
O'Brien, D. T., Ball, S., Sarfarazi, M., Harper, P. S., Robson, E. B. Genetic linkage between the loci for myotonic dystrophy and peptidase D. Ann. Hum. Genet. 47: 117-122, 1983. [PubMed: 6881909] [Full Text: https://doi.org/10.1111/j.1469-1809.1983.tb00978.x]
Pedersen, P. S., Christensen, E., Brandt, N. J. Prolidase deficiency. Acta Paediat. Scand. 72: 785-788, 1983. [PubMed: 6637477] [Full Text: https://doi.org/10.1111/j.1651-2227.1983.tb09815.x]
Royce, P. M., Steinmann, B. Prolidase deficiency.In: Royce, P. M.; Steinmann, B. (eds.) : Connective Tissue and its Heritable Disorders. New York: Wiley-Liss 2002. Pp. 727-738.
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Siciliano, M. J., Stallings, R. L., Adair, G. M., Humphrey, R. M., Siciliano, J. Provisional assignment of TPI, GPI, and PEPD to Chinese hamster autosomes 8 and 9: a cytogenetic basis for functional haploidy of an autosomal linkage group in CHO cells. Cytogenet. Cell Genet. 35: 15-20, 1983. [PubMed: 6825466] [Full Text: https://doi.org/10.1159/000131830]
Tanoue, A., Endo, F., Akaboshi, I., Oono, T., Arata, J., Matsuda, I. Molecular defect in siblings with prolidase deficiency and absence or presence of clinical symptoms: a 0.8-kb deletion with breakpoints at the short, direct repeat in the PEPD gene and synthesis of abnormal messenger RNA and inactive polypeptide. J. Clin. Invest. 87: 1171-1176, 1991. [PubMed: 2010534] [Full Text: https://doi.org/10.1172/JCI115115]
Tanoue, A., Endo, F., Kitano, A., Matsuda, I. A single nucleotide change in the prolidase gene in fibroblasts from two patients with polypeptide positive prolidase deficiency: expression of the mutant enzyme in NIH 3T3 cells. J. Clin. Invest. 86: 351-355, 1990. [PubMed: 2365824] [Full Text: https://doi.org/10.1172/JCI114708]
Tanoue, A., Endo, F., Matsuda, I. Structural organization of the gene for human prolidase (peptidase D) and demonstration of a partial gene deletion in a patient with prolidase deficiency. J. Biol. Chem. 265: 11306-11311, 1990. [PubMed: 1972707]
Wang, H., Kurien, B. T., Lundgren, D., Patel, N. C., Kaufman, K. M., Miller, D. L., Porter, A. C., D'Souza, A., Nye, L., Tumbush, J., Hupertz, V., Kerr, D. S., Kurono, S., Matsumoto, H., Scofield, R. H. A nonsense mutation of PEPD in four Amish children with prolidase deficiency. Am. J. Med. Genet. 140A: 580-585, 2006. [PubMed: 16470701] [Full Text: https://doi.org/10.1002/ajmg.a.31134]