Volume 54, Issue 3, Pages (September 1998)

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Volume 54, Issue 3, Pages 698-705 (September 1998) CLCN5 chloride-channel mutations in six new North American families with X-linked nephrolithiasis Richard R. Hoopes, Paul A. Hueber, Robert J. Reid, Gregory L. Braden, Paul R. Goodyer, Andrew R. Melnyk, Julian P. Midgley, Donald I. Moel, Alicia M. Neu, Scott K. VanWhy, Steven J. Scheinman Kidney International Volume 54, Issue 3, Pages 698-705 (September 1998) DOI: 10.1046/j.1523-1755.1998.00061.x Copyright © 1998 International Society of Nephrology Terms and Conditions

Figure 1 Segregation of the R28X mutation in Family A. The C-to-T base substitution disrupts an XhoI recognition sequence. Thus, when genomic DNA is amplified with exon-specific primers and digested with XhoI, this results in a product of 271bp rather than the normal product size of 228bp. Heterozyous females display both the mutant (m) and wild-type (wt) alleles, affected males display the mutant allele, and normal males the WT allele. This family includes carrier females I-1, with symptomatic recurrent nephrolithiasis, and I-2, with renal insufficiency and proteinuria. Kidney International 1998 54, 698-705DOI: (10.1046/j.1523-1755.1998.00061.x) Copyright © 1998 International Society of Nephrology Terms and Conditions

Figure 2 (Left panel) Segregation of the W343X mutation with disease in Family C. The C-to-T transition creates a BfaI recognition site, and the PCR-amplified exon (427bp) is digested to two fragments (258 and 169bp) with BfaI. Patient C-I-1 is a woman with nephrolithiasis who is heterozygous for this nonsense mutation. (Right panel) Segregation of the single base deletion at codon 44 with disease in Family E. The deletion of a single adenine, which leads to frameshift with premature termination of transcription, creates a BsrI restriction site. The PCR using primers flanking the exon 3 yield a product of 260bp in normal individuals, and digestion with BsrI produces two products of 126 and 134bp size which overlap in a single band on this 2% agarose gel. Kidney International 1998 54, 698-705DOI: (10.1046/j.1523-1755.1998.00061.x) Copyright © 1998 International Society of Nephrology Terms and Conditions

Figure 3 Transition of C to T at codon 34 in patient B. The resulting TGA nonsense codon leads to termination of transcription. Kidney International 1998 54, 698-705DOI: (10.1046/j.1523-1755.1998.00061.x) Copyright © 1998 International Society of Nephrology Terms and Conditions

Figure 4 Cleavase® fragment length polymorphism (CFLP) analyses. (Left panel) Deletion of A at codon 40 in exon 3 alters pattern of bands on CFLP analysis in patients D-II-1 (lane 1) and D-II-2 (lane 2) as compared with the normal pattern in lanes 4, 5, and 6. The exon in the patient represented in lane 6 was confirmed to be normal by sequencing. Patient E-II-1, with a different mutation in the same exon (deletion of A at codon 44), is represented in lane 3, where the pattern of bands differs as well. (Right panel) C-to-T transition at codon 244 in exon 7 in patient F (lane 1) alters the band indicated by the arrow as compared with normal samples in lanes 2, 3, and 4. Kidney International 1998 54, 698-705DOI: (10.1046/j.1523-1755.1998.00061.x) Copyright © 1998 International Society of Nephrology Terms and Conditions

Figure 5 Schematic summary of the amino acid sequence of the CLC-5 channel protein with predicted topology, revised from Lloyd et al2to indicate 27 mutations reported so far (2-4,8,9,11,17,18, and this report). These include 10 missense, 7 nonsense, and 6 frameshift mutations, in addition to 2 splice-site mutations, one intragenic deletion, and one in-frame insertion of a triplet encoding histidine. Not shown are two deletions of 515kb19 and 180kb9 encompassing the entire gene, so that a total of 29 mutations have been reported to date. The six mutations in the current report are indicated with asterisks (*), including S244L and W343X which had previously been reported in other families2,3,11,18. Kidney International 1998 54, 698-705DOI: (10.1046/j.1523-1755.1998.00061.x) Copyright © 1998 International Society of Nephrology Terms and Conditions

Kidney International 1998 54, 698-705DOI: (10. 1046/j. 1523-1755. 1998 Kidney International 1998 54, 698-705DOI: (10.1046/j.1523-1755.1998.00061.x) Copyright © 1998 International Society of Nephrology Terms and Conditions

Kidney International 1998 54, 698-705DOI: (10. 1046/j. 1523-1755. 1998 Kidney International 1998 54, 698-705DOI: (10.1046/j.1523-1755.1998.00061.x) Copyright © 1998 International Society of Nephrology Terms and Conditions