A common molecular basis for three inherited kidney stone diseases
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A common molecular basis for three inherited kidney stone diseases. / Lloyd, S E; Pearce, S H; Fisher, S E; Steinmeyer, K; Schwappach, B; Scheinman, S J; Harding, B; Bolino, A; Devoto, M; Goodyer, P; Rigden, S P; Wrong, O; Jentsch, T J; Craig, I W; Thakker, R V.
In: NATURE, Vol. 379, No. 6564, 01.02.1996, p. 445-9.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A common molecular basis for three inherited kidney stone diseases
AU - Lloyd, S E
AU - Pearce, S H
AU - Fisher, S E
AU - Steinmeyer, K
AU - Schwappach, B
AU - Scheinman, S J
AU - Harding, B
AU - Bolino, A
AU - Devoto, M
AU - Goodyer, P
AU - Rigden, S P
AU - Wrong, O
AU - Jentsch, T J
AU - Craig, I W
AU - Thakker, R V
PY - 1996/2/1
Y1 - 1996/2/1
N2 - Kidney stones (nephrolithiasis), which affect 12% of males and 5% of females in the western world, are familial in 45% of patients and are most commonly associated with hypercalciuria. Three disorders of hypercalciuric nephrolithiasis (Dent's disease, X-linked recessive nephrolithiasis (XRN), and X-linked recessive hypophosphataemic rickets (XLRH)) have been mapped to Xp11.22 (refs 5-7). A microdeletion in one Dent's disease kindred allowed the identification of a candidate gene, CLCN5 (refs 8,9) which encodes a putative renal chloride channel. Here we report the investigation of 11 kindreds with these renal tubular disorders for CLCN5 abnormalities; this identified three nonsense, four missense and two donor splice site mutations, together with one intragenic deletion and one microdeletion encompassing the entire gene. Heterologous expression of wild-type CLCN5 in Xenopus oocytes yielded outwardly rectifying chloride currents, which were either abolished or markedly reduced by the mutations. The common aetiology for Dent's disease, XRN and XLRH indicates that CLCN5 may be involved in other renal tubular disorders associated with kidney stones.
AB - Kidney stones (nephrolithiasis), which affect 12% of males and 5% of females in the western world, are familial in 45% of patients and are most commonly associated with hypercalciuria. Three disorders of hypercalciuric nephrolithiasis (Dent's disease, X-linked recessive nephrolithiasis (XRN), and X-linked recessive hypophosphataemic rickets (XLRH)) have been mapped to Xp11.22 (refs 5-7). A microdeletion in one Dent's disease kindred allowed the identification of a candidate gene, CLCN5 (refs 8,9) which encodes a putative renal chloride channel. Here we report the investigation of 11 kindreds with these renal tubular disorders for CLCN5 abnormalities; this identified three nonsense, four missense and two donor splice site mutations, together with one intragenic deletion and one microdeletion encompassing the entire gene. Heterologous expression of wild-type CLCN5 in Xenopus oocytes yielded outwardly rectifying chloride currents, which were either abolished or markedly reduced by the mutations. The common aetiology for Dent's disease, XRN and XLRH indicates that CLCN5 may be involved in other renal tubular disorders associated with kidney stones.
KW - Amino Acid Sequence
KW - Animals
KW - Base Sequence
KW - Calcium/urine
KW - Cells, Cultured
KW - Chloride Channels/chemistry
KW - DNA
KW - DNA Mutational Analysis
KW - Electrochemistry
KW - Female
KW - Kidney Calculi/genetics
KW - Male
KW - Molecular Sequence Data
KW - Mutation
KW - Pedigree
KW - Polymerase Chain Reaction
KW - Protein Conformation
KW - Recombinant Proteins/chemistry
KW - Xenopus
U2 - 10.1038/379445a0
DO - 10.1038/379445a0
M3 - SCORING: Journal article
C2 - 8559248
VL - 379
SP - 445
EP - 449
JO - NATURE
JF - NATURE
SN - 0028-0836
IS - 6564
ER -