A nonsense mutation of PEPD in four Amish children with prolidase deficiency.
Encoded by the peptidase D (PEPD) gene located at 19q12-q13.11, prolidase is a ubiquitous cytosolic enzyme that catalyzes hydrolysis of oligopeptides with a C-terminal proline or hydroxyproline. We describe here four Amish children with a severe phenotype of prolidase deficiency in the Geauga settlements of Ohio as the first report of prolidase deficiency in the Amish population as well as in the United States. The patients presented with infection, hepatosplenomegaly, or thrombocytopenia, in contrast to most cases previously reported in the literature, presenting with skin ulcers. All four patients had typical facial features, classic skin ulcers, and multisystem involvement. Recurrent infections, asthma-like chronic reactive airway disease, hyperimmunoglobulins, hepatosplenomegaly with mildly elevated aspartate transaminase (AST), anemia, and thrombocytopenia were common and massive imidodipeptiduria was universal. Prolidase activity in our patients is nearly undetectable. Direct sequencing of PCR-amplified genomic DNA for all of the exons from the four patients revealed the same homozygous single nucleotide mutation c.793 T > C in exon 11, resulting in a premature stop-codon at amino acid residue 265 (p.R265X). It is speculated that the severe phenotype in these patients might be associated with the type of the PEPD gene mutation.
Wang
Heng
H
Das Deutsch Center (DDC) Clinic for Special Needs Children, Middlefield, Ohio 44062, USA. wang@ddclinic.org
Kurien
Biji T
BT
Lundgren
David
D
Patel
Nisha C
NC
Kaufman
K M
KM
Miller
David L
DL
Porter
Andrew C
AC
D'Souza
Anil
A
Nye
Leah
L
Tumbush
John
J
Hupertz
Vera
V
Kerr
Douglas S
DS
Kurono
S
S
Matsumoto
H
H
Scofield
R Hal
RH
D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D001483:Base Sequence; D002648:Child; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004150:Dipeptidases / Q000097:blood / Q000172:deficiency / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics*; D005192:Family Health; D005260:Female; D006529:Hepatomegaly / Q000473:pathology; D006801:Humans; D008297:Male; D010375:Pedigree; D012883:Skin Ulcer / Q000473:pathology; D013163:Splenomegaly / Q000473:pathology
D018389:Codon, Nonsense; D004150:Dipeptidases; C022449:proline dipeptidase