A novel SLC12A1 mutation in Bedouin kindred with antenatal Bartter syndrome type I

Abstract

Four affected individuals of consanguineous kindred presented at infancy with an apparently autosomal recessive syndrome of polyuria and hypokalemic metabolic alkalosis, following maternal polyhydramnios and premature delivery, culminating in severe failure to thrive. Hypercalciuria, nephrocalcinosis, and hyperaldosteronism were further apparent as well as an unusual finding of intermittent hypernatremia. Additionally, all patients demonstrated variable micrognathia with upper respiratory airway abnormalities. As neither postnatal hyperkalemia nor permanent hearing deficits were shown, clinical assessment was consistent with antenatal Bartter syndrome (ABS) type I, which was never described before in the Israeli Bedouin population. Through genome‐wide linkage analysis, we identified a single ∼3.3 Mbp disease‐associated locus on chromosome 15q21.1, segregating within the pedigree. Whole‐exome sequencing revealed a single novel homozygous missense mutation within this locus, in SLC12A1, encoding the Na‐K‐Cl cotransporter, NKCC2, in accordance with the clinical diagnosis. In this concise study, we report a novel missense mutation within the SLC12A1 gene, causing a severe form of ABS type I, the first to be described in Israeli Bedouins, with unusual clinical features of hypernatremia caused by nephrogenic diabetes insipidus and putatively related micrognathia with upper airway abnormalities .

Cation-coupled chloride cotransporters: chemical insights and disease implications

“…More than 80 mutations of the SLC12A1 gene, which encodes for NKCC2, have been associated with Bartter syndrome (BS) type 1, a renal disorder characterized by polyuria, renal tubular hypokalemic alkalosis, hypercalciuria [71,72], and blood pressure alterations [60,73]. Other mutations in the NKCC2 TM and CT domains in antenatal/neonatal BS patients are associated with Trends in Chemistry OPEN ACCESS premature delivery, polyhydramnios, nephrocalcinosis, and hyperthyroidism [74][75][76][77][78]. Some of these mutations have been studied in vitro, showing low expression profile and lack of Na + transport [79].…”

“…Loss ion transport activity. [ 74 , 76 , 79 ] D699fs, W936X Salt-losing tubulopathy [ 80 ] R833Ifs, T931fsX10 Neonatal hyperparathyroidism [ 77 ] F747fs, E832A Blood pressure variation [ 73 ] (r)Y1066C, (r)P1079A ↓ Na uptake, no change in protein expression [ 60 ] KCC2 E50_Q93del NT EIMFS Impaired Cl extrusion. No change in membrane expression [ 88 ] A191V, L288H, L311H, W318S, S323P, S376L, M415V, L403P, L426P, G528D, G551D TM EIMFS A191V: impaired Cl extrusion.…”

Development and nationwide validation of kidney graft injury markers using urinary exosomes and microvesicles (complete English translation of the Japanese version)

“…SLC12A1 was identified as a candidate marker for reflecting the severity of IFTA by qPCR analysis. NKCC exists on the cell surface and has two variants, NKCC1 and NKCC2; NKCC2 is expressed only in kidney tissue and encoded by SLC12A1 [ 28 ]. However, the role of NKCC in graft fibrosis and tubular atrophy is not understood.…”

Partial penetrance and phenotypic variability of aplasia of lacrimal and salivary glands caused by a novel FGF10 donor splice‐site mutation

“…DNA was extracted per the manufacturer's protocol, using omega BIO‐TEK E.Z.N.A.® SQ Blood DNA Kit. Whole exomes of patients VI‐3 and VI‐8 were sequenced as previously described (Halperin et al, 2019). Data were analyzed using QIAGEN's Ingenuity Variant Analysis software (http://www.qiagen.com/ingenuity; QIAGEN Redwood City).…”