title: Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome.
abstract: In 11 patients with a recessive congenital disorder, which we refer to as "the hypotonia-cystinuria syndrome," microdeletion of part of the SLC3A1 and PREPL genes on chromosome 2p21 was found. Patients present with generalized hypotonia at birth, nephrolithiasis, growth hormone deficiency, minor facial dysmorphism, and failure to thrive, followed by hyperphagia and rapid weight gain in late childhood. Since loss-of-function mutations in SLC3A1 are known to cause isolated cystinuria type I, and since the expression of the flanking genes, C2orf34 and PPM1B, was normal, the extended phenotype can be attributed to the deletion of PREPL. PREPL is localized in the cytosol and shows homology with prolyl endopeptidase and oligopeptidase B. Substitution of the predicted catalytic residues (Ser470, Asp556, and His601) by alanines resulted in loss of reactivity with a serine hydrolase-specific probe. In sharp contrast to prolyl oligopeptidase and oligopeptidase B, which require both aminoterminal and carboxyterminal sequences for activity, PREPL activity appears to depend only on the carboxyterminal domain. Taken together, these results suggest that PREPL is a novel oligopeptidase, with unique structural and functional characteristics, involved in hypotonia-cystinuria syndrome.
authors.affiliation: Department of Paediatrics, University Hospitals Leuven, Belgium.
authors.forename: Jaak
authors.initials: J
authors.lastname: Jaeken
authors.forename: Kevin
authors.initials: K
authors.lastname: Martens
authors.forename: Inge
authors.initials: I
authors.lastname: Francois
authors.forename: Francois
authors.initials: F
authors.lastname: Eyskens
authors.forename: Claudine
authors.initials: C
authors.lastname: Lecointre
authors.forename: Rita
authors.initials: R
authors.lastname: Derua
authors.forename: Sandra
authors.initials: S
authors.lastname: Meulemans
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Slootstra
authors.forename: Etienne
authors.initials: E
authors.lastname: Waelkens
authors.forename: Francis
authors.initials: F
authors.lastname: de Zegher
authors.forename: John W M
authors.initials: JW
authors.lastname: Creemers
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
mesh_terms: D000595:Amino Acid Sequence; D026923:Amino Acid Transport Systems, Basic / Q000235:genetics; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D001483:Base Sequence; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D015152:Blotting, Northern; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D003555:Cystinuria / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D017353:Gene Deletion; D005808:Genes, Recessive; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009943:Organophosphorus Compounds / Q000378:metabolism; D000085822:Prolyl Oligopeptidases; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D013379:Substrate Specificity; D013577:Syndrome
chemical_list: C403065:10-(fluoroethoxyphosphinyl)-N-(biotinamidopentyl)decanamide; D026923:Amino Acid Transport Systems, Basic; D026921:Amino Acid Transport Systems, Neutral; D009943:Organophosphorus Compounds; C489857:SLC3A1 protein, human; D001710:Biotin; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases