title: Deletion of PREPl causes growth impairment and hypotonia in mice.
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.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Anna Mari
authors.initials: AM
authors.lastname: Lone
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Mathias
authors.initials: M
authors.lastname: Leidl
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: McFedries
authors.affiliation: Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America ; Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: James W
authors.initials: JW
authors.lastname: Horner
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: John
authors.initials: J
authors.lastname: Creemers
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000209:etiology / Q000235:genetics; D003555:Cystinuria / Q000209:etiology / Q000235:genetics; D005091:Exons / Q000235:genetics; D008607:Intellectual Disability / Q000209:etiology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D028361:Mitochondrial Diseases / Q000209:etiology / Q000235:genetics; D009123:Muscle Hypotonia / Q000209:etiology / Q000235:genetics; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000172:deficiency* / Q000235:genetics
chemical_list: D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases