NPHP3 – Renal-hepatic-pancreatic Dysplasia

NPHP3 encodes nephrocystin-3, a ciliary protein implicated in autosomal recessive renal-hepatic-pancreatic dysplasia (MONDO:0017417). Homozygous null alleles disrupt primary cilia function, leading to a Meckel-Gruber–like phenotype with cystic kidneys, ductal plate malformation in liver, and pancreatic dysplasia.

In a consanguineous family, two siblings presented with polycystic dysplastic kidneys incompatible with postnatal survival, liver ductal plate malformation, and pancreatic dysplasia; one had situs inversus totalis (HP:0001696). Homozygosity mapping identified a 21.16 Mb region on chromosome 3 containing NPHP3. Sequencing revealed homozygosity for a conserved splice-acceptor deletion, c.2694-2_2694-1del, which segregated with disease in both affected siblings (PMID:20007846).

Inheritance is autosomal recessive, with segregation of the homozygous splice-site deletion in two affected siblings and unaffected heterozygous parents.

The key pathogenic allele is c.2694-2_2694-1del, predicting loss of the splice acceptor before exon 20 and resulting in a null allele.

Functional studies in mouse models demonstrate that complete loss of Nphp3 function leads to embryonic lethality, situs inversus, congenital heart defects, and a Meckel-Gruber–like syndrome including renal-hepatic-pancreatic dysplasia. Nephrocystin-3 interacts with inversin to regulate canonical and noncanonical Wnt signaling; its deficiency disrupts planar cell polarity in Xenopus, concordant with human phenotype (PMID:18371931).

Integration of genetic and experimental data supports a pathogenic mechanism of loss of function. While only one family has been reported, the concordant mouse knockout phenotype and conserved ciliary role establish moderate clinical validity. Key take-home: NPHP3 screening for splice-site and loss-of-function variants is critical for diagnosis of renal-hepatic-pancreatic dysplasia.

References

• The Journal of Molecular Diagnostics • 2010 • Identification of a gene for renal-hepatic-pancreatic dysplasia by microarray-based homozygosity mapping. PMID:20007846
• American Journal of Human Genetics • 2008 • Loss of nephrocystin-3 function can cause embryonic lethality, Meckel-Gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia. PMID:18371931

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