A Tanoue, F Endo, I Akaboshi, T Oono, J Arata, and I Matsuda
Department of Pediatrics, Kumamoto University Medical School, Japan.
Prolidase deficiency is an autosomal recessive disorder with highly variable symptoms, including mental retardation, skin lesions, and abnormalities of collagenous tissues. In Japanese female siblings with polypeptide negative prolidase deficiency, and with different degrees of severity of skin lesions, we noted an abnormal mRNA with skipping of 192 bp sequence corresponding to exon 14 in lymphoblastoid cells taken from these patients. Transfection and expression analyses using the mutant prolidase cDNA revealed that a mutant protein translated from the abnormal mRNA had an Mr of 49,000 and was enzymatically inactive. A 774-bp deletion, including exon 14 was noted in the prolidase gene. The deletion had termini within short, direct repeats ranging in size of 7 bp (CCACCCT). The "slipped mispairing" mechanism may predominate in the generation of the deletion at this locus. This mutation caused a 192-bp in-frame deletion of prolidase mRNA and was inherited from the consanguineous parents. The same mutation caused a different degree of clinical phenotype of prolidase deficiency in this family, therefore factor(s) not related to the PEPD gene product also contribute to development of the clinical symptoms. Identification of mutations in the PEPD gene from subjects with prolidase deficiency provides further insight into the physiological role and structure-function relationship of this biologically important enzyme.
PEPTIDASE D; PEPD
Alternative titles; symbols
PROLIDASE DEFICIENCY, INCLUDED
Gene map locus 19cen-q13.11
See peptidase A (169800). Also called prolidase, imidodipeptidase, proline dipeptidase and aminoacyl-L-proline hydrolase, peptidase D (EC 188.8.131.52) specifically splits iminodipeptides with C-terminal proline or hydroxyproline, e.g., glycylproline. The enzyme prolinase (EC 184.108.40.206) splits iminodipeptides with N-terminal proline or hydroxyproline, e.g., prolylglycine. The 2 dipeptidases play an important role in collagen metabolism because of the high level of iminoacids in collagen (proline + hydroxyproline = 25%). Lewis and Harris (1969) identified a number of electrophoretic variants of peptidase D of red cells. Deficiency of prolidase has been described (see later); deficiency of prolinase is not known (Myara et al., 1984).
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 aregionalization 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. 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. This conclusion is inconsistent with that previously reported, which places the locus in the proximal part of the long arm of chromosome 19. Tanoue et al. (1990) demonstrated that the prolidase gene comprises 15 exons and 14 introns 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.
Powell et al. (1974) described a patient who excreted massive amounts of glycyl-L-proline and other di- and tri-peptides containing proline. Prolidase, the enzyme known to cleave the bond between the other amino acid and proline (which is carboxyl-terminal), was found to be absent or markedly decreased in the patient's red and white cells. The mother and maternal grandfather had intermediate levels. The father was not available for study. The parents were not known to be related. The proband was a 7-year-old white male with dry, cracked erythematous palms and soles and with obesity from an early age. Mild mental retardation and 'mild diffuse demineralization' of long bones were described.
Powell et al. (1975) studied 2 children with prolidase deficiency. Clinical features included chronic dermatitis, frequent infections, splenomegaly, and massive imidodipeptiduria. Powell et al. (1977) reported that chronic ear and sinus infections, chronic skin lesions, and splenomegaly were features. Sheffield et al. (1977) described an 11-year-old boy who was born of consanguineous parents and presented distinctive clinical features of recurrent skin ulceration, lymphedema, hepatosplenomegaly, and mild mental retardation. Massive amounts of dipeptides, most of which had proline or hydroxyproline as the carboxyl residue, were excreted in the urine. Glycylproline predominated. Prolidase deficiency was demonstrable in red cells, fibroblasts, and continuous lymphocyte cultures.
Myara et al. (1984) stated that about 20 cases of prolidase deficiency had been reported. Dermatologic features, particularly severe leg ulcers, and mental retardation of variable severity were the main manifestations (Der Kaloustian et al., 1982). Recurrent infections might be due to a disturbance of complement component C1q, which contains a large amount of iminoacids. Most patients have an unusual facial appearance as well as splenomegaly. After gelatin ingestion, excretion of iminoacids in the urine is increased, indicating that iminoacid absorption in the intestine is not modified even though prolidase is deficient in the intestine.
Freij et al. (1984) described affected brothers.
Leoni et al. (1987) described prolidase deficiency in 2 sisters who suffered from recurrent leg ulcers, which first appeared in early childhood. Milligan et al. (1989) described a patient in whom chronic leg ulceration was due to prolidase deficiency. They added erosive cystitis as a feature of the disorder. Multiple affected sibs, parental consanguinity, and equal sex distribution indicate recessive inheritance. Endo et al. (1987) found absence of a subunit of prolidase in red cells in a patient with prolidase deficiency.
Wysocki et al. (1988) described a 17-year-old girl with recurrent ulceration, initially covering most of her body but later in life confined mainly to her legs. Although she had an almost complete absence of prolidase in plasma and erythrocytes, this patient did not excrete hydroxyproline-containing dipeptides in her urine. One or more of the symptoms of prolidase deficiency may reflect a tissue deficiency of L-proline, which is not reclaimed in the absence of prolidase. Excretion of this amino acid, in bound form, can be as high as 20 to 30 mmol/day. Against the proposition that the failure of recovery of proline from iminodipeptides has a major role in the pathogenesis of prolidase deficiency is the fact that oral administration of L-proline does not relieve the dermatologic lesions. Attempts at enzyme replacement with normal matched erythrocytes have had no effect on iminodipeptiduria and this appears to be due to the fact that prolidase occurs in erythrocytes in an inactive form. Hechtman et al. (1988) found that brief exposure of intact erythrocytes to low concentrations of manganese ion activated intracellular prolidase without causing hemolysis. Hechtman et al. (1988) showed that erythrocytes so treated retained high levels of enzymatic activity for at least 2 weeks.
Ohhashi et al. (1988) reported prolidase serum activities against 6 different substrates from 2 patients with prolidase deficiency, their mother, and controls. Complementation studies indicate that a single genetic locus is involved; however, Boright et al. (1988) demonstrated 3 classes of mutant alleles. In 6 prolidase-deficient cell strains, Boright et al. (1989) identified 3 types of mutations: half the cell lines showed a mutation that conferred a CRM-negative phenotype, while the other 3 showed CRM-positive mutations of 2 types, 1 mutation encoding an enlarged subunit (60 kD as contrasted with the normal 58-kD polypeptide) and the others associated with subunits of normal size. Complementation analysis indicated that the mutations mapped to the same locus. Normal subjects and obligate heterozygotes expressing CRM-negative mutations had thermostable prolidase activity at 50 degrees C in cell extracts, whereas heterozygotes expressing CRM-positive mutations had thermolabile activity under the same conditions, implying negative allelic complementation in the putative heterodimer. Alternative enzymatic activity not encoded at the prolidase locus was indicated by the occurrence of prolidase-like activity about 5% of normal in amount but with a preference for substrate different from normal, in cells homozygous (or compound) for CRM-negative mutations. Allelic heterogeneity at the major locus and the amount of alternative peptidase activity encoded elsewhere appear to be determinants of the associated and heterogeneous clinical phenotype.
Endo et al. (1990) demonstrated great biochemical heterogeneity in prolidase deficiency. There was no apparent relation between the clinical symptoms and the biochemical phenotypes, except that mental retardation was present in the polypeptide-negative (CRM-negative) patients. Berardesca et al. (1992) reported the case of a 15-year-old boy with prolidase deficiency and marked urinary excretion of the iminodipeptide gly-pro. After blood transfusion, prolidase activity in erythrocytes against substrate glycyl-proline increased to 15.7% of donor activity and declined to 12% and 3.4% of normal activity after 8 and 45 days, respectively.
Urinary iminodipeptide levels following transfusion remained unaltered. Transfusions of concentrated erythrocytes led to at least partial healing of ulcers of the skin but these recurred by 18 months after the last transfusion.
Shrinath et al. (1997) described 2 children with prolidase deficiency who developed clinical and immunologic abnormalities consistent with a diagnosis of systemic lupus erythematosus (SLE; 152700). The first child died from septicemia, and SLE was diagnosed only during his terminal illness. As a result of this diagnosis, his cousin, who was already known to have prolidase deficiency, was investigated further and a diagnosis of SLE was confirmed. Following treatment with oral prednisolone her clinical condition improved, although she had a persistently raised erythrocyte sedimentation rate (ESR) and florid facial rash. Both prolidase deficiency and SLE are associated with disturbances in immune function and have clinical features in common.
Prolidase deficiency may be a risk factor for SLE. Shrinath et al. (1997) suggested that patients with SLE should be specifically investigated for prolidase deficiency, especially where there is a family history of SLE or presentation of SLE in childhood, since standard immunologic or hematologic investigations will not identify the biochemical abnormalities characteristic of prolidase deficiency.
Ledoux et al. (1994) described 4 mutant PEPD alleles associated with prolidase deficiency and Ledoux et al. (1996) reported 2 additional ones. Ledoux et al. (1996) developed a novel expression system to study mutant PEPD alleles by using COS-1 cells and demonstrated that 4 of these mutations were responsible for the enzyme deficiency.
In 5 cases of prolidase deficiency, Forlino et al. (2002) provided molecular characterization of 3 mutations, all of which resulted in loss of prolidase activity. Long-term cultured fibroblasts from the patients were used to develop an in vitro model that allowed investigation of the affected cells. Light and electron microscopy revealed that prolidase-deficient cells were more round and branched out than controls, and had increased cytosolic vacuolization, interruptions of the plasma membrane, mitochondrial swelling, and modifications of the mitochondrial matrix and cristae. Forlino et al. (2002) interpreted these findings as evidence that absence of prolidase activity causes the activation of a necrosis-like cellular death, which could be responsible for the skin lesions typical of prolidase deficiency.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
.0001 PROLIDASE DEFICIENCY [PEPD, ASP276ASN]
In 2 unrelated patients with polypeptide-positive (CRM-positive) prolidase deficiency, Tanoue et al. (1990) demonstrated a G-to-A substitution at nucleotide 826 in exon 12, resulting in replacement of aspartic acid by asparagine at amino acid residue 276. Both patients were homozygous for this mutation.
.0002 PROLIDASE DEFICIENCY [PEPD, EX14DEL]
Tanoue et al. (1990) analyzed DNA from 3 patients with prolidase deficiency by Southern blot analysis after TaqI or BamHI digestion. A partial deletion of several hundred basepairs, eliminating 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.
.0003 PROLIDASE DEFICIENCY [PEPD, ARG154GLN ]
In a prolidase deficiency individual asymptomatic at age 11 years, Ledoux et al. (1996) demonstrated compound heterozygosity for a G-to-A transition of nucleotide 551 in exon 8 (R184Q) and a G-to-A transition of nucleotide 833 in exon 123 (G278D; 170100.0004). To assess the biochemical phenotypes of these in 2 previously identified PEPD mutations (G448R; 170100.0005 and E452DEL; 170100.0006), 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.
.0004 PROLIDASE DEFICIENCY [PEPD, GLY278ASP ]
See 170100.0003 and Ledoux et al. (1996).
.0005 PROLIDASE DEFICIENCY [PEPD, GLY448ARG ]
See 170100.0003 and Ledoux et al. (1996). This same mutation was identified in 2 brothers by Forlino et al. (2002), who found that it resulted from a G-to-A transition at nucleotide 1342.
.0006 PROLIDASE DEFICIENCY [PEPD, 3-BP DEL, GLU452DEL ]
See 170100.0003 and Ledoux et al. (1996).
Butterwork and Priestman (1986); Endo et al. (1987); Martiniuk et al. (1985); Scriver et al. (1983); Tanoue et al. (1990)
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Linkage between the loci for peptidase D and apolipoprotein CII on chromosome 19. Ann. Hum. Genet. 49: 129-134, 1985.PubMed ID : 3000274
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Blood transfusions in the therapy of a case of prolidase deficiency. Brit. J. Derm. 126: 193-195, 1992.PubMed ID : 1536787
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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 ID : 318156
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Victor A. McKusick - updated : 11/13/2002Victor A. McKusick - updated : 6/26/1997
Online Mendelian Inheritance In Man
See Also: Prolidase Deficiency