The NPHP3 gene encodes for Nephrocystin 3, a protein involved in the negative regulation of canonical Wnt signaling pathway. The protein plays an important role in development and is involved in cilium assembly, kidney morphogenesis, determination of left/right symmetry, regulation of planar cell polarity (i.e. in neural tube closure) and maintenance of animal organ identity.
The gene has been implicated in three allelic overlapping disorders: Meckel syndrome 7 (MKS7), Nephronophthisis 3 (NPHP3) and Renal-Hepatic-Pancreatic Dysplasia 1 (RHPD1). MKS7 is lethal ciliopathy characterized by Dandy-Walker malformation, cystic kidney disease and hepatic abnormalities. NPHP3 is a milder autosomal recessive cystic kidney disease resulting in renal failure and hepatic fibrosis. RHPD1 is an often fatal disorder that results in abnormalities of the kidneys, liver, pancreas, heart, lungs, spleen and central nervous system.
The NPHP3 gene is located on the long arm of chromosome 3. It spans a length of 41.8 kb of DNA and its coding sequence is spread across 27 exons. The protein encoded by this gene is made up of 1330 amino acids and has a molecular mass of 150 kDa. Multiple isoforms of the NPHP3 protein exist due to alternative splicing. While the gene is widely expressed in the heart, placenta, liver, skeletal muscle, kidney and pancreas, it is overexpressed in the nasal epithelium and cerebrospinal fluid. Mutations in the gene associated with MKS7, Nephronophthisis 3 and RHPD1 include homozygous and compound heterozygous deletions, missense and nonsense mutations.
Al-Hamed et al. (2016) attempted to ascertain the underlying gene defects in a cohort of 44 Saudi families affected by antenatal cystic kidney disease. In one such family, antenatal ultrasound examination found the fetus to have cystic kidneys and congenital heart malformation. The case resulted in fetal death and DNA was unavailable for analysis. However, the consanguineous parents were both found to be heterozygous for the novel NPHP3 mutation c.2694-1_-2delAG. The deletion was predicted by ‘Human Splicing Finder’ to result in a broken acceptor site. It occurred at a conserved residue and had a minor allele frequency of 0.0003553 according to the ExAC database.