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.

Zdhhc13-dependent Drp1 S-palmitoylation impacts brain bioenergetics, anxiety, coordination and motor skills

“…Given that the genetic background of our luc mice (C57BL/6NJ) is different than the Zdhhc13 (Hip14l) KO mice utilized by Dr. Hayden’s group (FVB/N) 5 and that genetic background affects the appearance of phenotypes even when carrying the same mutations 16 , behavioral tests (including those representative of the HD’s phenotype) were administered to both HOM and HET mice (3-m old). The tests were chosen to evaluate disease-specific and gene dose-dependent behaviors, including motor function, endurance, and gait [rotarod 17 , footprint analysis 18 ]; learning and memory [fear conditioning 18 ]; anxiety-related behavior [open field 17 , 19 , 20 ]; reduction of muscle strength/hypotonia [grip strength 21 ]; and schizophrenia/schizophrenia-like disorders [prepulse inhibition test 20 ].…”

“…The grip strength was employed to assess the neuromuscular function as maximal muscle strength of forelimbs and combined forelimbs and hind limbs 21 .…”

PREPL Deficiency: A Homozygous Splice Site PREPL Mutation in a Patient With Congenital Myasthenic Syndrome and Absence of Ovaries and Hypoplasia of Uterus

“…Previous studies have reported that PREPL is expressed widely across many tissue types (Jaeken et al, 2006;Boonen et al, 2011). The established function of PREPL is to redistribute clathrin-associated adaptor protein complex 1(AP-1) from the cell membrane into the cytoplasm; AP-1 mediates the transport of vesicular acetylcholine transporter (Lone et al, 2014). PREPL deficiency causes a reduction in the filling of ACh synaptic vesicles (Régal et al, 2014).…”

Anxiety risk SNPs on chromosome 2 modulate arousal in children in a fear generalization paradigm

“…Motor learning and complex coordination and learning of aversive stimuli are also impaired, pointing to the possibility that CAMKMT could be a reasonable candidate for further experiments. Knockout mice for PREPL suffer neonatal hypotonia and diminished growth [40] making this gene a less likely candidate, similarly to SLC3A1 null mice displaying cystinuria [41]. Further experiments are needed to investigate how these human SNPs might be associated with anxiety and arousal and what biological mechanisms are associated with this phenotype.…”