title: Mutations in exons 3 and 7 resulting in truncated expression of human ATP6V1B1 gene showing structural variations contributing to poor substrate binding-causative reason for distal renal tubular acidosis with sensorineural deafness.
abstract: Distal renal tubular acidosis (dRTA) is an autosomal recessive syndrome results defect in either proximal tubule bicarbonate reabsorption or in distal tubule H(+) secretion and is characterized by severe hyperchloraemic metabolic acidosis in childhood. dRTA is associated with functional variations in the ATP6V1B1 gene encoding β1 subunit of H(+)-ATPase, key membrane transporters for net acid excretion of α-intercalated cells of medullary collecting ducts. In the present study, a 13-year-old male patient suffering with nephropathy and sensorineural deafness was reported in the Department of Nephrology. We predicted improper functioning of ATP6V1B1 gene could be the reason for diseased condition. Therefore, exons 3, 4, and 7 contributing active site of ATP6V1B1 gene was amplified and sequenced (Accession numbers: KF571726, KM222653). The obtained sequences were BLAST searched against the wild type ATP6V1B1 gene which showed novel mutations c.307 A > G, c.308 C > A, c.310 C > G, c.704 T > C, c.705 G > T, c.709 A > G, c.710 A > G, c.714 G > A, c.716 C > A, c.717delC, c.722 C > G, c.728insG, c.741insT, c.753G > C. These mutations resulted in the expression of truncated protein terminating at Lys 209. The mutated ATP6V1B1structure superimposed with wild type showed extensive variations with RMSD 1.336 Å and could not bind to substrate ADP leading to non-functional ATPase. These results conclusively explain these mutations in ATP6V1B1 gene resulted in structural changes causing accumulation of H(+) ions contributing to dRTA with sensorineural deafness.
authors.affiliation: a Department of Biotechnology , Sri Venkateswara Institute of Medical Sciences , Tirupati , AP 517507 , India.
authors.forename: Pasupuleti Santhosh
authors.initials: PS
authors.lastname: Kumar
authors.forename: Katari
authors.initials: K
authors.lastname: Venkatesh
authors.forename: Gopal
authors.initials: G
authors.lastname: Sowjenya
authors.forename: Lokanathan
authors.initials: L
authors.lastname: Srikanth
authors.forename: Manne Mudhu
authors.initials: MM
authors.lastname: Sunitha
authors.forename: Uppu Venkateswara
authors.initials: UV
authors.lastname: Prasad
authors.forename: Vimjam
authors.initials: V
authors.lastname: Swarupa
authors.forename: Sthanikam
authors.initials: S
authors.lastname: Yeswanth
authors.forename: P Sri Ram
authors.initials: PS
authors.lastname: Naveen
authors.forename: A
authors.initials: A
authors.lastname: Sridhar
authors.forename: V Siva
authors.initials: VS
authors.lastname: Kumar
authors.forename: P V G K
authors.initials: PV
authors.lastname: Sarma
mesh_terms: D000141:Acidosis, Renal Tubular / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000244:Adenosine Diphosphate / Q000737:chemistry*; D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D018389:Codon, Nonsense; D005091:Exons; D015870:Gene Expression; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D025262:Vacuolar Proton-Translocating ATPases / Q000737:chemistry* / Q000235:genetics
chemical_list: C509766:ATP6V1B1 protein, human; D018389:Codon, Nonsense; D000244:Adenosine Diphosphate; D025262:Vacuolar Proton-Translocating ATPases
keywords: ADP; ATP6V1B1; RMSD; dRTA; mutations