The XPNPEP3 gene is located on chromosome at 22q13.2 and encodes a member of the family of X-pro-aminopeptidases that utilize a metal cofactor and remove the N-terminal amino acid from peptides with a proline residue in the penultimate position. This protein has been shown to localize to the mitochondria of kidney cells and have a role in ciliary function. (provided by RefSeq, Mar 2011).
XPNPEP3 was first reported in relation to autosomal recessive Nephronophthisis-like Nephropathy 1 (NPHPL1) in 2010 (O'Toole et al. PMID: 20179356). The mechanism of disease is biallelic loss of function. Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Variants in this gene have been reported in at least 6 probands in 5 publications (PMID: 29383790, 32660933,37599822,38035175, DOI: 10.1681/ASN.20233411S1571a). Unpublished data was included in this curation, a patient with a consistent phenotype associated with compound heterozygous null variants (Molecular Biology Laboratory, Fundació Puigvert and submitted to ClinVar), increasing the final score by 3.0 points for a total of 11.3 genetic evidence points.
This gene-disease association is supported by protein interaction, in vitro functional assays, and a zebrafish and a mouse model (PMID: 20179356, 37599822). There is significant correlation between β-catenin nuclear localization and XPNPEP3 levels, suggesting XPNPEP3 has a role in Wnt-mediated regulation of ciliary development (Kumar et al. 2018; PMID: 29383790, non-scorable evidence).
In summary, there is Definitive evidence to support XPNPEP3 as a cause of an autosomal recessive ciliopathy. This gene-disease pair was originally evaluated by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on 04/28/2021 (SOP Version 8). It was reevaluated on 6/10/2024 (SOP Version 10). As a result of this reevaluation, the classification changed from Moderate to Definitive.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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