Abstract
Genetic studies of rare diseases can identify genes of unknown function that strongly impact human physiology. Prolyl endopeptidase-like (PREPL) is an uncharacterized member of the prolyl peptidase family that was discovered because of its deletion in humans with hypotonia-cystinuria syndrome (HCS). HCS is characterized by a number of physiological changes including diminished growth and neonatal hypotonia or low muscle tone. HCS patients have deletions in other genes as well, making it difficult to tease apart the specific role of PREPL. Here, we develop a PREPL null (PREPL−/−) mouse model to address the physiological role of this enzyme. Deletion of exon 11 from the Prepl gene, which encodes key catalytic amino acids, leads to a loss of PREPL protein as well as lower Prepl mRNA levels. PREPL−/− mice have a pronounced growth phenotype, being significantly shorter and lighter than their wild type (PREPL+/+) counterparts. A righting assay revealed that PREPL−/− pups took significantly longer than PREPL+/+ pups to right themselves when placed on their backs. This deficit indicates that PREPL−/− mice suffer from neonatal hypotonia. According to these results, PREPL regulates growth and neonatal hypotonia in mice, which supports the idea that PREPL causes diminished growth and neonatal hypotonia in humans with HCS. These animals provide a valuable asset in deciphering the underlying biochemical, cellular and physiological pathways that link PREPL to HCS, and this may eventually lead to new insights in the treatment of this disease.
Highlights
Interest in the prolyl endopeptidase-like gene (PREPL) was sparked by the discovery that this gene associated with 2p21 deletion syndrome [1,2] and with hypotonia-cystinuria syndrome (HCS) [3,4,5]
Isolated deletions of SLC3A1, which is highly expressed in the kidney [7], are known to cause cystinuria [8], suggesting that Prolyl endopeptidase-like (PREPL) is accountable for the other symptoms associated with HCS
Exon 11 of the Prepl gene, which contains the catalytic serine nucleophile, was placed between two Cre recombinase recognition sites (LoxP sites) [22] (Fig. 1A). This would allow for the tissue- or age-specific removal of PREPL catalytic activity, if necessary
Summary
Interest in the prolyl endopeptidase-like gene (PREPL) was sparked by the discovery that this gene associated with 2p21 deletion syndrome [1,2] and with hypotonia-cystinuria syndrome (HCS) [3,4,5]. HCS presents clinically as decreased muscle tone (hypotonia) as well as excess cystine in the urine (cystinuria), but other symptoms such as diminished growth and mild mental retardation are associated with HCS. HCS is associated the deletion of other genes besides PREPL. In some atypical HCS cases, PREPL and SLC3A1 are deleted with another gene, calmodulin-lysine Nmethyltransferase (CAMKMT or C2ORF34) [6]. Isolated deletions of SLC3A1, which is highly expressed in the kidney [7], are known to cause cystinuria [8], suggesting that PREPL is accountable for the other symptoms associated with HCS. PREPL deletion is thought to cause neonatal hypotonia [3] and impaired growth [9], but this has yet to be confirmed by a deletion of PREPL alone
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