Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome. 1638 48

Deletion of the Prolyl Endopeptidase-like (PREPL) gene has been described in three contiguous gene deletion syndromes at the 2p21 locus and current developments in high resolution microarrays and whole genome sequencing will no doubt soon result in the identification of isolated PREPL deficiency. But by comparing the differences in phenotypes with the number of genes deleted, the contribution of PREPL deficiency can already be deduced. Homozygous or compound heterozygous loss of PREPL is predicted to cause neonatal hypotonia and severe feeding problems. Failure to thrive usually persists for several years, followed by a period of hyperphagia and excessive weight gain. Growth retardation is usually observed, which responds well to growth hormone therapy. In addition, minor facial dysmorphism, nasal speech, viscous saliva, hypergonadotropic hypogonadism and learning problems are frequently observed. How PREPL deficiency causes these clinical manifestations remains unknown. PREPL is highly expressed in brain and based on gene coexpression network architecture it has been placed in a group enriched with markers of neurons and synaptic proteins. PREPL is predicted to be a serine oligopeptidase based on its homology with prolyl endopeptidase (PREP) and the presence of an active catalytic triad. However, until now no substrates have been found. Recent observations that PREP has non-catalytic functions in the cytoplasm through interactions with its amino- terminal propeller domain, suggests that of PREPL may also have biological functions independent of its predicted peptidase activity. This raises the possibility that PREP and PREPL are homologous, not just by name but also by nature.
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PMID:PREPL, a prolyl endopeptidase-like enzyme by name only?--Lessons from patients. 2122 27