Novel compound heterozygous ATP6V1B1 mutations in a Chinese child patient with primary distal renal tubular acidosis: a case report

Abstract

Background: Distal renal tubular acidosis (dRTA) is a heterogeneous disorder characterized by normal anion gap metabolic acidosis. Autosomal recessive dRTA is usually caused by mutations occurring in ATP6V1B1 and ATP6V0A4 genes,encoding subunits B1 and a4 of apical H⁺-ATPase, respectively. The heterogeneous clinical manifestations of dRTA have been described in different ethnic groups harboring distinct mutations. Most of the reported cases are from Europe and Africa. At present, the prevalence of primary dRTA is still poorly elucidated in Chinese population.

Case presentation: A 2-year and six-month-old female patient was hospitalized because of recurrent hypokalemia, hyperchloremic metabolic acidosis and growth retardation. Laboratory investigations presented a normal anion gap hyperchloremic metabolic acidosis, hypokalemia, and inappropriate alkaline urine. Renal ultrasound indicated bilateral nephrocalcinosis. Bilateral sensorineural hearing loss (SNHL) was confirmed with moderately severe (45 dB) on the left ear and severe (80 dB) on the right ear, which was accompanied with enlarged vestibular aqueduct (EVA) on both sides. According to these findings, a diagnosis of dRTA was made. To identify the pathogenic gene mutation, all coding regions of ATP6V1B1 and ATP6V0A4 gene, including intron-exon boundaries, were analyzed using PCR followed by direct sequence analysis. The splicing variants were verified in peripheral blood leucocytes of the patient by RT-PCR. As a result, two novel heterozygous mutations in ATP6V1B1 were identified in the child. One mutation was a successive 2-nucleotide deletion in exon 2(c.133-134delTG), which caused a marked nonsense mediated mRNA decay. The other was a guanine to adenine substitution of the first nucleotide of intron 8(c.785 + 1 G > A), which led to the exclusion of exon 8. After treatment with sodium citrate, potassium citrateand citric acid, metabolic acidosis and hypokalemia were corrected, but her hearing decreased gradually during the 2 years and had to accept the use of bilateral hearing aids.

Conclusions: We described two novel dRTA associated mutations in ATP6V1B1 identified in a Chinese child patient accompanying with SNHL and EVA. Our study will help to expand the understanding of this rare disease in Chinese population.

Keywords: ATP6V1B1 gene; Distal renal tubular acidosis; Enlarged vestibular aqueduct; Sensorineural hearing loss.

Fig. 1

High-resolution computed tomography indicated bilateral enlargement of the vestibular aqueduct

Fig. 2

Two novel ATP6V1B1 mutations identified in a Chinese patient with dRTA. a Partial nucleotide sequence of the wild type and the successive 2-nucleotide deletion in exon 2(c.133-134delTG). The arrow indicated the position of deleted TG in exon 2. b The guanine to adenine substitution of the first nucleotide of intron 8(c.785 + 1 G > A). The arrow indicated the position of G > A mutation in intron 8

Fig. 3

The verification of exon 8 skipping in the peripheral white cells of the patient. The cDNA segment containing exon 7, 8 and 9 of ATP6V1B1 were amplified by nested PCR as above-described. a Electrophoresis of the PCR products from normal control or the patient. b Sequencing chromatogram of the PCR products from normal person (correct splice product) or the patient (exon 8 skipping)

Fig. 4

Growth curve of the patient