title: 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: BACKGROUND
  Distal 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.
  
  
  METHODS
  The 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Departments of Medical Genetics, Renal Medicine and Ophthalmology, University of Cambridge, Cambridge, UK. een22@cam.ac.uk.|Cambridge Institute for Medical Research, Box 139, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK. een22@cam.ac.uk.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Norgett
authors.affiliation: Departments of Medical Genetics, Renal Medicine and Ophthalmology, University of Cambridge, Cambridge, UK. anthony.yii@cantab.net.
authors.forename: Anthony
authors.initials: A
authors.lastname: Yii
authors.affiliation: Departments of Medical Genetics, Renal Medicine and Ophthalmology, University of Cambridge, Cambridge, UK. kgb24@cantab.net.|Cambridge Institute for Medical Research, Box 139, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK. kgb24@cantab.net.
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Blake-Palmer
authors.affiliation: Pediatric Nephrology Research Center, Pediatric Infections Research Centre (PIRC), Shaheed Beheshti University of Medical Sciences, Tehran, Iran. sharifian.dorche@gmail.com.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Sharifian
authors.affiliation: Departments of Medical Genetics, Renal Medicine and Ophthalmology, University of Cambridge, Cambridge, UK. louise.allen@addenbrookes.nhs.uk.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Allen
authors.affiliation: Azad University Medical Branch, Tehran, Iran. hamidnajafi20@gmail.com.
authors.forename: Abdolhamid
authors.initials: A
authors.lastname: Najafi
authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Centre, Tehran, Iran. arianakariminejad@yahoo.com.
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.affiliation: Departments of Medical Genetics, Renal Medicine and Ophthalmology, University of Cambridge, Cambridge, UK. fek1000@cam.ac.uk.|Cambridge Institute for Medical Research, Box 139, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK. fek1000@cam.ac.uk.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Karet Frankl
mesh_terms: D000141:Acidosis, Renal Tubular / Q000235:genetics* / Q000503:physiopathology*; D000328:Adult; D001483:Base Sequence; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D012160:Retina / Q000503:physiopathology*; D017384:Sequence Deletion
chemical_list: D018398:Homeodomain Proteins; C492362:VAX2 protein, human