Clustering of private mutations in the congenital chloride diarrhea/down‐regulated in adenoma gene

Höglund, Pia; Haila, Siru; Gustavson, Karl‐Henrik; Taipale, Mikko; Hannula, Katariina; Popińska, Katarzyna; Holmberg, Christer; Socha, Jerzy; Chapelle, Albert de la; Kere, Juha

doi:10.1002/(sici)1098-1004(1998)11:4<321::aid-humu10>3.3.co;2-1

Cited by 7 publications

(14 citation statements)

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“…4F). All these mutations are considered novel except for the G187X mutation, which is a known founder mutation for congenital chloride diarrhea in Saudi Arabia (24). None of these mutations were found in sequencing of 190 control chromosomes from unrelated Caucasian subjects.…”

Section: Mutation In Slc26a3mentioning

confidence: 99%

Genetic diagnosis by whole exome capture and massively parallel DNA sequencing

Choi

Scholl²,

Ji³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

1,184

876

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Protein coding genes constitute only approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., ''whole exome'') have the potential to contribute to the understanding of rare and common human diseases. Here we report a method for whole-exome sequencing coupling Roche/NimbleGen whole exome arrays to the Illumina DNA sequencing platform. We demonstrate the ability to capture approximately 95% of the targeted coding sequences with high sensitivity and specificity for detection of homozygous and heterozygous variants. We illustrate the utility of this approach by making an unanticipated genetic diagnosis of congenital chloride diarrhea in a patient referred with a suspected diagnosis of Bartter syndrome, a renal salt-wasting disease. The molecular diagnosis was based on the finding of a homozygous missense D652N mutation at a position in SLC26A3 (the known congenital chloride diarrhea locus) that is virtually completely conserved in orthologues and paralogues from invertebrates to humans, and clinical follow-up confirmed the diagnosis. To our knowledge, whole-exome (or genome) sequencing has not previously been used to make a genetic diagnosis. Five additional patients suspected to have Bartter syndrome but who did not have mutations in known genes for this disease had homozygous deleterious mutations in SLC26A3. These results demonstrate the clinical utility of whole-exome sequencing and have implications for disease gene discovery and clinical diagnosis.Bartter syndrome ͉ congenital chloride diarrhea ͉ next-generation sequencing ͉ whole-exome sequencing ͉ personal genomes G enetic variation plays a major role in both Mendelian and non-Mendelian diseases. Among the approximately 2,600 Mendelian diseases that have been solved, the overwhelming majority are caused by rare mutations that affect the function of individual proteins; at individual Mendelian loci, approximately 85% of the disease-causing mutations can typically be found in the coding region or in canonical splice sites (1). For complex traits, genome-wide association studies have identified more than 250 common variants associated with risk alleles that contribute to a wide range of diseases (2, 3). To date, most of these impart small effects on disease risk (e.g., odds ratio of 1.2); moreover, even when extremely large studies have been performed, the vast majority of the genetic contribution to disease risk remain unexplained (4-6). These findings suggest that individually rare variants with relatively large effect may account for a large fraction of this missing trait variance. Indeed, studies addressing this question have documented the presence of individually rare variants with relatively large effect (7,8). Consistent with the Mendelian model, coding variants have proven to be prevalent sources of such rare variants.These considerations motivate implementation of robust approaches to sequencing complete c...

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Section: Mutation In Slc26a3mentioning

confidence: 99%

Genetic diagnosis by whole exome capture and massively parallel DNA sequencing

Choi

Scholl²,

Ji³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

1,184

876

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“…4). The Finnish founder mutation is a 3-bp in-frame deletion that occurs on every CLD chromosome in Finland except one (78). Interestingly, when the Luria-Delbrück formula is used to calculate the age of the mutation (g) the other parameters including genetic distance being known, the average value of g obtained for five markers in the region turns out to be 19 (range [13][14][15][16][17][18][19][20][21][22][23][24][25].…”

Section: Chloride Diarrhea (Cld)mentioning

confidence: 99%

“…The locus was assigned by linkage analysis to a 10-cM region, and every CLD chromosome in Finland occurred on the same, extended haplotype, suggesting a single founding mutation (␣ ϭ 1) (27,77). The critical region was narrowed to approximately 0.37 cM by linkage disequilibrium analysis, and this region contained two previously cloned genes, one of which, down-regulated in adenoma (DRA), turned out to be responsible for the disease (28).…”

Section: Chloride Diarrhea (Cld)mentioning

confidence: 99%

“…Genetic drift, selection, and other factors can complicate fine-scale mapping and produce unreliable estimates (89)(90)(91). However, the apparent success of linkage disequilibrium mapping in several diseases (33,72,77,81,92,93) has demonstrated the feasibility of the approach in certain settings and inspired further methodological work.…”

Section: Statistical Issuesmentioning

confidence: 99%

See 1 more Smart Citation

Linkage disequilibrium mapping in isolated populations: The example of Finland revisited

Chapelle

Wright²

1998

Proc. Natl. Acad. Sci. U.S.A.

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201

105

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Linkage disequilibrium analysis can provide high resolution in the mapping of disease genes because it incorporates information on recombinations that have occurred during the entire period from the mutational event to the present. A circumstance particularly favorable for high-resolution mapping is when a single founding mutation segregates in an isolated population. We review here the population structure of Finland in which a small founder population some 100 generations ago has expanded into 5.1 million people today. Among the 30-odd autosomal recessive disorders that are more prevalent in Finland than elsewhere, several appear to have segregated for this entire period in the ''panmictic'' southern Finnish population. Linkage disequilibrium analysis has allowed precise mapping and determination of genetic distances at the 0.1-cM level in several of these disorders. Estimates of genetic distance have proven accurate, but previous calculations of the confidence intervals were too small because sampling variation was ignored. In the north and east of Finland the population can be viewed as having been ''founded'' only after 1500. Disease mutations that have undergone such a founding bottleneck only 20 or so generations ago exhibit linkage disequilibrium and haplotype sharing over long genetic distances (5-15 cM). These features have been successfully exploited in the mapping and cloning of many genes. We review the statistical issues of fine mapping by linkage disequilibrium and suggest that improved methodologies may be necessary to map diseases of complex etiology that may have arisen from multiple founding mutations.

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“…Mutations in the DRA gene manifest as congenital chloride diarrhea (CLD), an autosomal recessive disorder of intestinal electrolyte absorption (14,15). Studies of humans with CLD provide strong evidence for defects in Cl Ϫ /HCO 3 Ϫ exchange in the ileum and colon (16).…”

mentioning

confidence: 99%

The functional and physical relationship between the DRA bicarbonate transporter and carbonic anhydrase II

Sterling

Brown

Supuran

et al. 2002

American Journal of Physiology-Cell Physiology

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terminal cytoplasmic tails of chloride/bicarbonate anion exchangers (AE) bind cytosolic carbonic anhydrase II (CAII) to form a bicarbonate transport metabolon, a membrane protein complex that accelerates transmembrane bicarbonate flux. To determine whether interaction with CAII affects the downregulated in adenoma (DRA) chloride/bicarbonate exchanger, anion exchange activity of DRA-transfected HEK-293 cells was monitored by following changes in intracellular pH associated with bicarbonate transport. DRA-mediated bicarbonate transport activity of 18 Ϯ 1 mM H ϩ equivalents/min was inhibited 53 Ϯ 2% by 100 mM of the CAII inhibitor, acetazolamide, but was unaffected by the membrane-impermeant carbonic anhydrase inhibitor, 1-[5-sulfamoyl-1,3,4-thiadiazol-2-yl-(aminosulfonyl-4-phenyl)]-2,6-dimethyl-4-phenyl-pyridinium perchlorate. Compared with AE1, the COOH-terminal tail of DRA interacted weakly with CAII. Overexpression of a functionally inactive CAII mutant, V143Y, reduced AE1 transport activity by 61 Ϯ 4% without effect on DRA transport activity (105 Ϯ 7% transport activity relative to DRA alone). We conclude that cytosolic CAII is required for full DRA-mediated bicarbonate transport. However, DRA differs from other bicarbonate transport proteins because its transport activity is not stimulated by direct interaction with CAII. metabolon; chloride/bicarbonate exchanger; downregulated in adenoma BICARBONATE METABOLISM is essential in humans, because carbon dioxide is the metabolic end product of respiratory oxidation and CO 2 /HCO 3 Ϫ is the body's primary pH buffer system. The bicarbonate transport superfamily of genes (SLC4 and SLC26 gene families), responsible for transmembrane movement of membrane-impermeant HCO 3 Ϫ , comprises the Cl Ϫ /HCO 3 Ϫ anion exchanger (AE) family (1,19,20), the Na ϩ /HCO 3 Ϫ cotransporter proteins (NBC) (3, 4), and the recently identified proteins pendrin (9, 32, 37) and downregulated in adenoma (DRA) (23, 27, 48).Several lines of evidence have demonstrated an interaction between cytosolic carbonic anhydrase II (CAII) and the AE1, AE2, and AE3 anion exchanger isoforms. Binding of erythrocyte membranes to CAII increased CAII enzymatic activity (25), which suggests an interaction between these two proteins. CAII can be coimmunoprecipitated with solubilized AE1 and incubation with an extracellular lectin-caused agglutination of AE1 and a similar redistribution of CAII on the cytosolic surface of the erythrocyte membrane (45). A sensitive microtiter binding assay, using truncation and point mutation of the AE1 COOH terminus, led to the identification of the binding site of CAII in AE1 as LDADD (amino acids 886-890) (46) and the basic amino-terminal region of CAII as the binding site for AE1 (44).The functional consequences of the AE/CAII interaction have been studied (42). Using HEK-293 cells transiently transfected with AE1 cDNA, we determined that inhibition of endogenous CAII activity with acetazolamide resulted in a decrease of AE1 transport activity. Mutation of the AE1, LDADD, and CA...

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Clustering of private mutations in the congenital chloride diarrhea/down‐regulated in adenoma gene

Cited by 7 publications

References 0 publications

Genetic diagnosis by whole exome capture and massively parallel DNA sequencing

Genetic diagnosis by whole exome capture and massively parallel DNA sequencing

Linkage disequilibrium mapping in isolated populations: The example of Finland revisited

The functional and physical relationship between the DRA bicarbonate transporter and carbonic anhydrase II

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