On this page
PREPL
prolyl endopeptidase like
PREPL is located on the short (p) arm of chromosome 2, at band 2p21. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 2 in the library →Available at Jeen Health
Clinical tests that include this
Overview
PREPL is located on chromosome 2 and encodes a member of the prolyl oligopeptidase family. Despite its structural similarity to peptidase enzymes, the PREPL protein appears to have lost classical enzymatic activity during evolution, and researchers are still working to define its exact cellular functions. The gene is clinically relevant in the context of carrier screening because individuals who inherit two pathogenic variants may develop hypotonia-cystinuria syndrome, a rare condition characterised by reduced muscle tone and abnormal urinary amino acid excretion. Understanding carrier status for PREPL variants helps inform reproductive planning for couples at risk of having an affected child.
What the gene does
The PREPL protein belongs to the prolyl oligopeptidase family, a group of enzymes that typically cleave peptide bonds adjacent to proline residues. However, PREPL itself lacks detectable catalytic activity in standard biochemical assays, suggesting it may have evolved a different role. Research indicates that PREPL may function as a regulatory protein rather than an active peptidase, potentially modulating other enzymes or participating in protein-protein interactions within cells. The protein is expressed in various tissues, including skeletal muscle and kidney, where it may contribute to maintaining normal cellular homeostasis. Some evidence suggests PREPL could influence metabolic pathways or cellular signalling, though the mechanistic details remain an active area of investigation. The loss of PREPL function in individuals with biallelic pathogenic variants appears to disrupt muscle development and renal tubular processes, hinting at its importance in these physiological systems.
Video: Genetics 101
Chromosome location
PREPL is located on the short arm of chromosome 2 at position 2p21. The gene spans a genomic region that includes multiple exons encoding the 727-amino-acid protein. Notably, PREPL lies in close proximity to the SLC3A1 gene, and deletions affecting both genes can lead to a contiguous gene deletion syndrome with overlapping clinical features from loss of both gene products.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The PREPL sequence contains regions with homology to the alpha-beta hydrolase fold typical of prolyl oligopeptidases, yet key catalytic residues found in active family members are altered or absent in PREPL. This structural divergence likely accounts for the lack of enzymatic activity and suggests the protein has been repurposed for a non-catalytic function during evolution.
Key variants
Pathogenic variants in PREPL are typically loss-of-function changes, including nonsense mutations, frameshift insertions or deletions, and larger genomic deletions that remove part or all of the gene. Because PREPL-related conditions follow autosomal recessive inheritance, carriers with a single pathogenic variant generally remain asymptomatic. Disease manifests only when an individual inherits pathogenic variants from both parents, leading to severely reduced or absent PREPL protein function.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in PREPL are associated with hypotonia-cystinuria syndrome, a rare disorder characterised by neonatal or infantile hypotonia, growth delays, and elevated urinary cystine excretion. The syndrome often results from contiguous deletions affecting both PREPL and the neighbouring SLC3A1 gene, combining features of isolated PREPL deficiency with cystinuria. Individuals with isolated PREPL variants may present with milder phenotypes focused on muscle tone abnormalities and developmental concerns. The rarity of these conditions means that clinical understanding continues to evolve as additional cases are reported.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PREPL variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
PREPL is included on the NHS Genomic Medicine Service Developmental Disorders Genomics Programme panel with green classification, reflecting confidence in the gene-disease association for relevant presentations. This inclusion supports the use of PREPL testing in clinical diagnostic pathways for children and adults with unexplained hypotonia or related developmental concerns within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of a PREPL variant?
Carriers have one pathogenic PREPL variant and one working copy of the gene, which is typically sufficient for normal function. Carriers do not usually develop symptoms but can pass the variant to their children.
How is PREPL-related hypotonia-cystinuria syndrome inherited?
The condition follows autosomal recessive inheritance, meaning a child must inherit a pathogenic variant from both parents to be affected. When both parents are carriers, each pregnancy has a 25% chance of resulting in an affected child.
Is PREPL testing available through the NHS?
PREPL is included on NHS diagnostic panels for developmental disorders, and testing may be offered when clinical features suggest a relevant condition. Carrier screening for PREPL is also available through accredited laboratories for reproductive planning purposes.