A novel SLC4A1 variant in an autosomal dominant distal renal tubular acidosis family with a severe phenotype

Abstract

Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger AE1, cause distal renal tubular acidosis (dRTA), a disease of defective urinary acidification by the distal nephron. We searched for SLC4A1 gene mutations in six patients from a Chinese family with a severe phenotype of dRTA (growth impairment, severe metabolic acidosis, with/or without gross nephrocalcinosis and renal impairment). All coding regions of kidney isoform of AE1, including intron-exon boundaries, were analyzed using PCR followed by direct sequence analysis. A novel 1-bp duplication at nucleotide 2713 (c.2713dupG, band 3 Qingdao) in exon 20 of SLC4A1 in this family was identified by direct sequencing analysis. This duplication alters the encoded protein through codon 905, and results in a reading frame for 15 extra condons (instead of 8) before the new stop condon at position 919 (p.Asp905Glyfs15). We suggest that RTA should be considered as a diagnostic possibility in adult subjects with nephrocalcinosis and chronic renal insufficiency, and family survey should be carefully performed.

Structure, Function, and Trafficking of SLC4 and SLC26 Anion Transporters

“…In agreement with these findings, some of the latest dRTA mutations identified are either point or frameshift mutations within the short carboxyl-terminus of AE1 (Fry et al, 2012;Shao et al, 2010;Zhang et al, 2012). Additionally, they are all dominantly inherited and do not cause erythroid symptoms.…”

“…Insertion of single base results in frameshift and novel 15-amino acid C-terminal sequence to residue 919 (Shao et al, 2010) M909T Dominant Functional Mislocalized to both apical and basolateral membranes (Fry et al, 2012) as five amino acids from the C-terminus of AE1 impaired ER exit, while deletion of 20 residues profoundly decreased protein stability and expression (Cordat, Li, & Reithmeier, 2003). In agreement with these findings, some of the latest dRTA mutations identified are either point or frameshift mutations within the short carboxyl-terminus of AE1 (Fry et al, 2012;Shao et al, 2010;Zhang et al, 2012).…”

Mutation analysis and audiologic assessment in six Chinese children with primary distal renal tubular acidosis

“…The coding region and adjacent intronic segments of the ATP6V1B1 and SLC4A1 genes were amplified using of previously described primer pairs, respectively. 2,14 PCRs were performed in 50 lL of solution containing 0.2 mM dNTP, 0.03 U/lL Taq polymerase (Takara EX Taq Hot start version, DRR006B, Osaka, Japan), 2.0 mM MgCl 2 , 2.5 lL 10 Â PCR Mg 2+ -free buffer (Takara), approximately 50 ng genomic DNA and 1 mM of each primer. PCR was performed with an initial denaturation step at 95 C for 5 min, subsequently followed by 33 cycles with denaturation at 95 C for 45 s, annealing at 52-66 C for 45 s and elongation at 72 C for 45 s. PCR samples were subjected to bidirectional sequencing.…”

“…[1][2][3] Both autosomal dominant (AD) and autosomal recessive (AR) inheritance patterns have been reported in primary dRTA. Mutations in the ATP6V1B1 and ATP6V0A4 genes, encoding subunits B1 and a4 of apical H + -ATPase, cause recessive forms of dRTA.…”

Functional Rescue of a Kidney Anion Exchanger 1 Trafficking Mutant in Renal Epithelial Cells

“…AE1 is also expressed in red blood cells (eAE1) where it plays a crucial role in respiration. Up to 16 mutations in the SLC4A1 gene have been identified that cause dRTA [3]–[6]. Interestingly, some mutations in the SLC4A1 gene cause hereditary spherocytosis (HS), a common form of inherited haemolytic anemia, but the same mutation rarely causes both HS and dRTA.…”