PREPL – Hypotonia-Cystinuria Syndrome

Hypotonia-cystinuria syndrome (HCS) is a rare autosomal recessive contiguous gene deletion disorder at chromosome 2p21, characterized by neonatal hypotonia, cystinuria, growth hormone deficiency, muscle weakness, ptosis, feeding difficulties, and failure to thrive. HCS results from biallelic loss of PREPL and SLC3A1, with isolated PREPL deficiency manifesting as a congenital myasthenic syndrome with similar neuromuscular and endocrine features.

Genetic evidence for PREPL in HCS is robust. In an initial cohort of 11 unrelated probands with recessive microdeletions spanning SLC3A1 and PREPL, all exhibited hypotonia, nephrolithiasis, growth hormone deficiency, and failure to thrive ([PMID:16385448]). A global survey identified one recurrent deletion in six families and several rare alleles in 14 additional families ([PMID:17579669]). Segregation of PREPL null variants was observed in at least six additional affected relatives across multiple sibships ([PMID:21686663], [PMID:23794250]). The variant spectrum comprises large contiguous deletions and predicted null alleles, including nonsense and splice-site changes such as c.1261C>T (p.Arg421Ter).

Functional studies corroborate PREPL pathogenicity through neuromuscular transmission defects. Histochemical and immunoblot analyses of patient muscle demonstrated absent PREPL at endplates, with electrophysiology revealing decreased quantal content and reduced miniature endplate potential amplitude in isolated PREPL deficiency and HCS patients ([PMID:24610330]). Transient improvement with pyridostigmine in infancy supports a presynaptic defect amenable to cholinesterase inhibition.

Biochemical and animal models define PREPL as a serine (thio)esterase critical for mitochondrial homeostasis. Prepl knockout mice display reduced mitochondrial complex activities, abnormal ultrastructure, and disrupted mitochondrial gene expression mirroring human pathology. Structural elucidation of PREPL’s crystal structure and catalytic domain provides mechanistic insight into its loss-of-function effects ([PMID:34888501]).

Recent work expands the disease mechanism beyond simple catalytic loss. Functional characterization of three CMS22-associated missense variants revealed preserved hydrolase activity but impaired protein–protein interactions affecting Golgi trafficking, indicating that nonenzymatic roles of PREPL contribute to pathology ([PMID:39078710]).

Collectively, extensive genetic, segregation, and concordant functional data establish PREPL as definitively associated with hypotonia-cystinuria syndrome. Clinical testing for PREPL deletions and loss-of-function variants informs diagnosis, enables early therapeutic trials with cholinesterase inhibitors, and guides patient management.

References

• American Journal of Human Genetics • 2006 • Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome PMID:16385448
• European Journal of Human Genetics • 2007 • Global distribution of the most prevalent deletions causing hypotonia-cystinuria syndrome PMID:17579669
• BMJ Case Reports • 2009 • Deletion of C2orf34, PREPL and SLC3A1 causes atypical hypotonia-cystinuria syndrome PMID:21686663
• American Journal of Medical Genetics Part A • 2013 • Further delineation of genotype-phenotype correlation in homozygous 2p21 deletion syndromes: first description of patients without cystinuria PMID:23794250
• Neurology • 2014 • PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome PMID:24610330
• iScience • 2021 • Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function PMID:34888501
• JCI Insight • 2024 • Missense variants in CMS22 patients reveal that PREPL has both enzymatic and nonenzymatic functions PMID:39078710

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