Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database

Abstract

Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed.

Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

“…This result is well fitting with the fact that this couple underwent another TOP for severe renal hypoplasia in a second fetus (whose DNA was not available). Interestingly, this report is the second report of somatic mosaicism for a PAX2 mutation (16). Finally, the PAX2 p.Ile428Met missense change identified in one fetus with cystic dysplasia of a single kidney and uterine agenesis may not be responsible for this phenotype, but we were unable to obtain DNA from the unaffected parents to determine inheritance.…”

“…When no deletion was found, the nine exons and all exon-intron boundaries of the gene were screened by direct sequencing as previously described (15). PAX2 was tested in 75 unrelated fetuses (16 families were not tested: 11 families with an HNF1B mutation and 5 cases for which we no longer had DNA) by direct sequencing of the 12 coding exons as described previously (16). Reference sequences (http://www.hgvs.…”

The zebrafish eye—a paradigm for investigating human ocular genetics

“…PAX2 mutations are one of the most commonly identified genetic causes of renal-coloboma syndrome. 18 Zebrafish mutants which are homozygous for pax2a mutations exhibit optic fissure closure defects and lack the midbrain, midbrain-hindbrain boundary, and cerebellum, fail to feed and die within 2 weeks. 19 This optic fissure closure defect has been attributed in part, to the inhibition of downstream effector caspases and deficiencies in the control of cellular proliferation, implicating a role for pax2a in the fine tuning of apoptotic cell death.…”

Mutations in PAX2 Associate with Adult-Onset FSGS

“…Two of the variants isolated in FSGS families (p.Arg1043 and p.Thr164Asn) were previously identified in patients with CAKUT, with p.Thr164Asn considered benign. 13 In the FSGS families, the mutation of interest was documented in all affected individuals where DNA was available. Incomplete penetrance was documented in one family (Supplemental Figure 1).…”

“…The C-terminal half of the protein contains a partial so-called homeodomain that can function as a second DNA-binding motif, or as a protein-protein interaction motif, and a transactivation domain, which regulates gene transcription. 13,[16][17][18][19][20] Three of the FSGS missense mutations, p.Arg56Gln, p.Pro80Leu, and p.Ser133Phe, affected residues located in the paired domain near the N terminus of the protein.…”