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.

Global distribution of the most prevalent deletions causing hypotonia–cystinuria syndrome

“…1 Details are listed in Table 1. In summary, the clinical picture is characterized by neonatal and infantile hypotonia, and anorexia, often necessitating nasogastric tube feeding or gastrostomy.…”

“…As mutations in SLC3A1 cause isolated cystinuria type I and the flanking genes are normally expressed, the extended phenotype can be attributed to PREPL. 1 A larger deletion of 179 kb at this locus has previously been reported, 3,4 which causes the recessive 2p21 deletion syndrome. At least four genes (SLC3A1, PREPL, PPM1B and C2orf34) are deleted, resulting in a much more severe phenotype.…”

“…Primers used for amplifying deletions A and B have been described. 1 Primers for deletion E are 5 0 -TTGCTCCAAAAGTTCCTAACCAA-3 0 and 5 0 -TTCTGTGTTGAGGTTGCACTCC-3 0 .…”

“…1,2 Recently, the genetic defect underlying this syndrome has been characterized in nine families. 1 The disease is due to microdeletions that disrupt two genes on chromosome 2p21, SLC3A1 and PREPL.…”

“…1,2 Recently, the genetic defect underlying this syndrome has been characterized in nine families. 1 The disease is due to microdeletions that disrupt two genes on chromosome 2p21, SLC3A1 and PREPL. As mutations in SLC3A1 cause isolated cystinuria type I and the flanking genes are normally expressed, the extended phenotype can be attributed to PREPL.…”