A role for VAX2 in correct retinal function revealed by a novel genomic deletion at 2p13.3 causing distal Renal Tubular Acidosis: case report

Abstract

BackgroundDistal Renal Tubular Acidosis is a disorder of acid-base regulation caused by functional failure of α-intercalated cells in the distal nephron. The recessive form of the disease (which is usually associated with sensorineural deafness) is attributable to mutations in ATP6V1B1 or ATP6V0A4, which encode the tissue-restricted B1 and a4 subunits of the renal apical H+-ATPase. ATP6V1B1 lies adjacent to the gene encoding the homeobox domain protein VAX2, at 2p13.3. To date, no human phenotype has been associated with VAX2 mutations.Case presentationThe male Caucasian proband, born of a first cousin marriage, presented at 2 months with failure to thrive, vomiting and poor urine output. No anatomical problems were identified, but investigation revealed hyperchloremic metabolic acidosis with inappropriately alkaline urine and bilateral nephrocalcinosis. Distal Renal Tubular Acidosis was diagnosed and audiometry confirmed hearing loss at 2 years. ATP6V0A4 was excluded from genetic causation by intragenic SNP linkage analysis, but ATP6V1B1 completely failed to PCR-amplify in the patient, suggesting a genomic deletion. Successful amplification of DNA flanking ATP6V1B1 facilitated systematic chromosome walking to ascertain that the proband harbored a homozygous deletion at 2p13.3 encompassing all of ATP6V1B1 and part of VAX2; gene dosage was halved in the parents. This results in the complete deletion of ATP6V1B1 and disruption of the VAX2 open reading frame. Later ocular examinations revealed bilateral rod / cone photoreceptor dystrophy and mild optic atrophy. Similar changes were not detected in an adult harbouring a disruptive mutation in ATP6V1B1.ConclusionsThe genomic deletion reported here is firstly, the only reported example of a whole gene deletion to underlie Distal Renal Tubular Acidosis, where the clinical phenotype is indistinguishable from that of other patients with ATP6V1B1 mutations; secondly, this is the first reported example of a human VAX2 mutation and associated ocular phenotype, supporting speculation in the literature that VAX2 is important for correct retinal functioning.

Inherited Eye Diseases with Retinal Manifestations through the Eyes of Homeobox Genes

“…Bilateral rod/cone photoreceptor dystrophy and mild optic atrophy in the patient, with complete deletion of ATP6V1B1 and disruption of the VAX2 open reading frame, was revealed. Similar changes were not detected in an adult harboring a disruptive mutation in ATP6V1B1 usually associated with distal renal tubular acidosis [288].…”

First insights into the expression of VAX2 in humans and its localization in the adult primate retina

“…photoreceptors, remain to be further investigated. Of note, a recent study suggests an involvement of VAX2 in the photoreceptors biology in humans (Norgett et al, 2015). This case report described a patient harbouring a homozygous deletion at 2p13.3 encompassing all of ATP6V1B1 and part of VAX2; the patient was reported affected by Distal Renal Tubular Acidosis, however, amongst other features, he showed an ocular phenotype diagnosed as bilateral rod/cone photoreceptor dystrophy and mild optic atrophy (Norgett et al, 2015).…”

“…Of note, a recent study suggests an involvement of VAX2 in the photoreceptors biology in humans (Norgett et al, 2015). This case report described a patient harbouring a homozygous deletion at 2p13.3 encompassing all of ATP6V1B1 and part of VAX2; the patient was reported affected by Distal Renal Tubular Acidosis, however, amongst other features, he showed an ocular phenotype diagnosed as bilateral rod/cone photoreceptor dystrophy and mild optic atrophy (Norgett et al, 2015). Moreover, it should be mentioned that the photoreceptor outer segment is considered a specialized primary cilium and trafficking through the photoreceptor cilium is a highly regulated phenomenon (Hsiao et al, 2012;Yildiz and Khanna, 2012).…”

“…Moreover, very recently a homozygous deletion at 2p13.3 encompassing all of ATP6V1B1 and part of VAX2 has been reported in a patient affected by Distal Renal Tubular Acidosis. Interestingly, the patient, amongst other features, showed an ocular phenotype diagnosed as bilateral rod/cone photoreceptor dystrophy and mild optic atrophy (Norgett et al, 2015). It has been shown that Vax2 is also involved in correct intra-retinal M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 retinoic acid distribution, and its action extends to the mature retina, in particular to ensure appropriate gene expression in cone photoreceptor cells (Alfano et al, 2011).…”

Renal tubular acidosis in pediatrics: A review article

“…ATP6V0A4 was excluded from genetic causation by intragenic SNP linkage analysis, but ATP6V1B1 completely failed to PCR-amplify in the patient, suggesting a genomic deletion. 31…”