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Juha Kere - One of the best experts on this subject based on the ideXlab platform.
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congenital Chloride Diarrhea and pendred syndrome case report of siblings with two rare recessive disorders of slc26 family genes
BMC Medical Genetics, 2020Co-Authors: Eva Lindberg, Juha Kere, Satu Wedenoja, Claes Moller, Agneta AnderzencarlssonAbstract:Congenital Chloride Diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic Diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.
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update on slc26a3 mutations in congenital Chloride Diarrhea
Human Mutation, 2011Co-Authors: Satu Wedenoja, Juha Kere, Christer Holmberg, Pia Hoglund, Siru Makela, Elina PekansaariAbstract:Congenital Chloride Diarrhea (CLD) is an autosomal recessive disorder with around 250 cases reported so far. Life-long secretory Diarrhea is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene disrupting the epithelial Cl−/HCO transport in the ileum and colon. Although salt substitution allows favorable outcome, possible manifestations include renal impairment, intestinal inflammation, and male infertility. At least 55 mutations, of which 21 (38%) novel are reported here, cause CLD. Majority of the mutations are single nucleotide substitutions (n = 30; 55%) with 18 missense, 7 nonsense, and 5 splice-site mutations. Additional mutations are minor deletions/insertions or their combinations (n = 21; 38%), major deletions (n = 3; 5%), and a major insertion (n = 1; 2%). Distinct founder mutations appear in Finland, Poland, and Arab countries, whereas patients from other countries carry rare homozygous or compound heterozygous mutations. None of the studied SLC26A3 mutants shows significant Cl−/HCO exchange activity in vitro, and accordingly, evidence of genotype–phenotype differencies remain nonexistent. The domain interaction between SLC26A3 and the cystic fibrosis transmembrane conductance regulator (CFTR) raises a possibility of CFTR modulation in the pathogenesis of CLD. This review summarizes the current knowledge of SLC26A3 mutations and polymorphisms, and their biological and clinical relevance. Hum Mutat 32:1–8, 2011. © 2011 Wiley-Liss, Inc.
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the impact of sodium Chloride and volume depletion in the chronic kidney disease of congenital Chloride Diarrhea
Kidney International, 2008Co-Authors: Satu Wedenoja, Juha Kere, Christer Holmberg, Timo Ormala, Ulla B Berg, Stella Edstrom Halling, Hannu Jalanko, Riitta Karikoski, Pia HoglundAbstract:Congenital Chloride Diarrhea is due to mutations in the intestinal Cl − /HCO 3 − exchange (SLC26A3) which results in sodium Chloride and fluid depletion leading to hypochloremic and hypokalemic metabolic alkalosis. Although treatment with sodium and potassium Chloride offers protection from renal involvement in childhood, the long-term renal outcome remains unclear. Here we describe two cases of congenital Chloride Diarrhea-associated end-stage renal disease with transplantation. Further, we show that there is a high incidence of mild chronic kidney disease in 35 other patients with congenital Chloride Diarrhea. The main feature of the renal injury was nephrocalcinosis, without hypercalciuria or nephrolithiasis with small sized kidneys and commensurately reduced glomerular filtration rates. This suggests that Diarrhea-related sodium Chloride and volume depletion, the first signs of non-optimal salt substitution, promote urine supersaturation and crystal precipitation. The poor compliance with salt substitution along with long-lasting hypochloremic and hypokalemic metabolic alkalosis is likely to induce progressive calcification and renal failure. Both our patients developed nephrocalcinosis in the transplanted kidneys suggesting that this complication is a consequence of intestinal SLC26A3 deficiency. Interestingly, the transporter is expressed in the distal nephron but the recurrence of nephrocalcinosis in the transplanted kidney suggests that it does not play a significant renal role in this syndrome.
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slc26a3 mutations in congenital Chloride Diarrhea
Human Mutation, 2002Co-Authors: Siru Makela, Juha Kere, Christer Holmberg, Pia HoglundAbstract:Congenital Chloride Diarrhea (CLD) is an autosomal recessive disorder of intestinal electrolyte absorption. It is characterized by persistent secretory Diarrhea resulting in polyhydramnios and prematurity prenatally, and dehydration, hypoelectrolytemia, hyperbilirubinemia, abdominal distention, and failure to thrive immediately after birth. CLD is caused by mutations in the solute carrier family 26, member 3 gene (SLC26A3, alias CLD or DRA), which encodes a Na+-independent Cl−/HCO3− (or OH−) exchanger. SLC26A3 is a member of the SLC26 sulfate permease/anion transporter family and it is expressed mainly in the apical brush border of intestinal epithelium. The only extraintestinal tissues showing SLC26A3 expression are eccrine sweat glands and seminal vesicles. A wide variety of different mutations in the SLC26A3 gene have been associated with CLD with no apparent evidence of phenotype–genotype correlation. The clinical course of CLD, however, is variable and may rather depend on environmental factors and compensatory mechanisms than mutations. In this report, we present a summary of all published and two novel SLC26A3 mutations and polymorphisms, and review them in the context of their functional consequences and clinical implications. Hum Mutat 20:425–438, 2002. © 2002 Wiley-Liss, Inc.
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the congenital Chloride Diarrhea gene is expressed in seminal vesicle sweat gland inflammatory colon epithelium and in some dysplastic colon cells
Histochemistry and Cell Biology, 2000Co-Authors: Siru Haila, Ulpu Saarialhokere, Marjaliisa Karjalainenlindsberg, Kristiina Airola, Juha Kere, Christer Holmberg, Hannes Lohi, Johanna Hastbacka, Pia HoglundAbstract:Congenital Chloride Diarrhea (CLD) is an autosomal recessive disorder of intestinal electrolyte transportation caused by mutations in the anion transporter protein encoded by the down-regulated in adenoma (DRA), or CLD, gene. In this study, in situ hybridization and immunohistochemistry were performed to investigate the expression of CLD in extraintestinal normal epithelia and in intestinal inflammatory and neoplastic epithelia. The expression of the closely related anion transporter diastrophic dysplasia sulfate transporter, DTDST, was also examined and compared with that of CLD in colon. The only extraintestinal tissues showing CLD expression were eccrine sweat glands and seminal vesicles. In inflammatory bowel disease and ischemic colitis, expression of CLD mRNA in colon epithelium was similar to histologically normal colon epithelium, but the protein was found deeper in crypts, including proliferative epithelial cells. In intestinal tumors, the expression pattern of CLD was dependent on the differentiation status of the tissue studied: epithelial polyps with no or minor dysplasia showed abundant expression, whereas adenocarcinomas were negative. The DTDST gene was abundantly expressed in the upper crypt epithelium of colonic mucosa.
Pia Hoglund - One of the best experts on this subject based on the ideXlab platform.
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A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR
Scientific Reports, 2017Co-Authors: Satu Wedenoja, Christer Holmberg, Pia Hoglund, Ahlam Khamaysi, Liana Shimshilashvili, Shireen Anbtawe-jomaa, Outi Elomaa, Jorma Toppari, Kristiina Aittomäki, Outi HovattaAbstract:Chloride absorption and bicarbonate excretion through exchange by the solute carrier family 26 member 3 (SLC26A3) and cystic fibrosis transmembrane conductance regulator (CFTR) are crucial for many tissues including sperm and epithelia of the male reproductive tract. Homozygous SLC26A3 mutations cause congenital Chloride Diarrhea with male subfertility, while homozygous CFTR mutations cause cystic fibrosis with male infertility. Some homozygous or heterozygous CFTR mutations only manifest as male infertility. Accordingly, we studied the influence of SLC26A3 on idiopathic infertility by sequencing exons of SLC26A3 in 283 infertile and 211 control men. A heterozygous mutation c.2062 G > C (p.Asp688His) appeared in nine (3.2%) infertile men, and additionally, in two (0.9%) control men, whose samples revealed a sperm motility defect. The p.Asp688His mutation is localized in the CFTR-interacting STAS domain of SLC26A3 and enriched in Finland, showing a significant association with male infertility in comparison with 6,572 Finnish ( P
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update on slc26a3 mutations in congenital Chloride Diarrhea
Human Mutation, 2011Co-Authors: Satu Wedenoja, Juha Kere, Christer Holmberg, Pia Hoglund, Siru Makela, Elina PekansaariAbstract:Congenital Chloride Diarrhea (CLD) is an autosomal recessive disorder with around 250 cases reported so far. Life-long secretory Diarrhea is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene disrupting the epithelial Cl−/HCO transport in the ileum and colon. Although salt substitution allows favorable outcome, possible manifestations include renal impairment, intestinal inflammation, and male infertility. At least 55 mutations, of which 21 (38%) novel are reported here, cause CLD. Majority of the mutations are single nucleotide substitutions (n = 30; 55%) with 18 missense, 7 nonsense, and 5 splice-site mutations. Additional mutations are minor deletions/insertions or their combinations (n = 21; 38%), major deletions (n = 3; 5%), and a major insertion (n = 1; 2%). Distinct founder mutations appear in Finland, Poland, and Arab countries, whereas patients from other countries carry rare homozygous or compound heterozygous mutations. None of the studied SLC26A3 mutants shows significant Cl−/HCO exchange activity in vitro, and accordingly, evidence of genotype–phenotype differencies remain nonexistent. The domain interaction between SLC26A3 and the cystic fibrosis transmembrane conductance regulator (CFTR) raises a possibility of CFTR modulation in the pathogenesis of CLD. This review summarizes the current knowledge of SLC26A3 mutations and polymorphisms, and their biological and clinical relevance. Hum Mutat 32:1–8, 2011. © 2011 Wiley-Liss, Inc.
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three cases of a rare disease congenital Chloride Diarrhea summons up the variation in the clinical course and significance of early diagnosis and adequate treatment in the prevention of intellectual disability
Turkish Journal of Pediatrics, 2011Co-Authors: Figen Gurakan, Satu Wedenoja, Hasan Ozen, Gokhan Baysoy, Nuray Uslu, Fatih Ozaltin, Pia HoglundAbstract:Congenital Chloride Diarrhea (CLD) (OMIM #214700) is a rare, autosomal recessive disease that is characterized by increased Chloride loss in stool. As a result of electrolyte loss, surviving patients might have some complications, one of them being mental retardation. Here, we present three new Turkish patients with new mutations in the SLC26A3 gene. Although the clinical picture of the patients might be similar, consequences of the disease and complications might differ greatly among patients. Pediatricians should be aware of CLD as a potentially fatal or disabling disease if untreated. History of polyhydramnios, watery Diarrhea, failure to thrive, poor growth, soiling, metabolic alkalosis and hypokalemia/hypochloremia should be an alarming set of findings for the diagnosis. Salt substitution therapy started early in life prevents early complications, allows normal growth and development, and favors good long-term prognosis.
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the impact of sodium Chloride and volume depletion in the chronic kidney disease of congenital Chloride Diarrhea
Kidney International, 2008Co-Authors: Satu Wedenoja, Juha Kere, Christer Holmberg, Timo Ormala, Ulla B Berg, Stella Edstrom Halling, Hannu Jalanko, Riitta Karikoski, Pia HoglundAbstract:Congenital Chloride Diarrhea is due to mutations in the intestinal Cl − /HCO 3 − exchange (SLC26A3) which results in sodium Chloride and fluid depletion leading to hypochloremic and hypokalemic metabolic alkalosis. Although treatment with sodium and potassium Chloride offers protection from renal involvement in childhood, the long-term renal outcome remains unclear. Here we describe two cases of congenital Chloride Diarrhea-associated end-stage renal disease with transplantation. Further, we show that there is a high incidence of mild chronic kidney disease in 35 other patients with congenital Chloride Diarrhea. The main feature of the renal injury was nephrocalcinosis, without hypercalciuria or nephrolithiasis with small sized kidneys and commensurately reduced glomerular filtration rates. This suggests that Diarrhea-related sodium Chloride and volume depletion, the first signs of non-optimal salt substitution, promote urine supersaturation and crystal precipitation. The poor compliance with salt substitution along with long-lasting hypochloremic and hypokalemic metabolic alkalosis is likely to induce progressive calcification and renal failure. Both our patients developed nephrocalcinosis in the transplanted kidneys suggesting that this complication is a consequence of intestinal SLC26A3 deficiency. Interestingly, the transporter is expressed in the distal nephron but the recurrence of nephrocalcinosis in the transplanted kidney suggests that it does not play a significant renal role in this syndrome.
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long term clinical outcome in patients with congenital Chloride Diarrhea
Journal of Pediatric Gastroenterology and Nutrition, 2006Co-Authors: Satu Hihnala, Pia Hoglund, Timo Ormala, Laura Lammi, Jorma Kokkonen, Christer HolmbergAbstract:ABSTRACTObjectives:Congenital Chloride Diarrhea (CLD) is a rare, autosomal recessive disorder of intestinal Cl−/HCO3− exchange caused by mutations in the SLC26A3 gene and characterized by persistent Cl− rich Diarrhea from birth. Treatment is symptomatic and replacement therapy with NaCl and KCl has
Christer Holmberg - One of the best experts on this subject based on the ideXlab platform.
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A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR
Scientific Reports, 2017Co-Authors: Satu Wedenoja, Christer Holmberg, Pia Hoglund, Ahlam Khamaysi, Liana Shimshilashvili, Shireen Anbtawe-jomaa, Outi Elomaa, Jorma Toppari, Kristiina Aittomäki, Outi HovattaAbstract:Chloride absorption and bicarbonate excretion through exchange by the solute carrier family 26 member 3 (SLC26A3) and cystic fibrosis transmembrane conductance regulator (CFTR) are crucial for many tissues including sperm and epithelia of the male reproductive tract. Homozygous SLC26A3 mutations cause congenital Chloride Diarrhea with male subfertility, while homozygous CFTR mutations cause cystic fibrosis with male infertility. Some homozygous or heterozygous CFTR mutations only manifest as male infertility. Accordingly, we studied the influence of SLC26A3 on idiopathic infertility by sequencing exons of SLC26A3 in 283 infertile and 211 control men. A heterozygous mutation c.2062 G > C (p.Asp688His) appeared in nine (3.2%) infertile men, and additionally, in two (0.9%) control men, whose samples revealed a sperm motility defect. The p.Asp688His mutation is localized in the CFTR-interacting STAS domain of SLC26A3 and enriched in Finland, showing a significant association with male infertility in comparison with 6,572 Finnish ( P
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update on slc26a3 mutations in congenital Chloride Diarrhea
Human Mutation, 2011Co-Authors: Satu Wedenoja, Juha Kere, Christer Holmberg, Pia Hoglund, Siru Makela, Elina PekansaariAbstract:Congenital Chloride Diarrhea (CLD) is an autosomal recessive disorder with around 250 cases reported so far. Life-long secretory Diarrhea is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene disrupting the epithelial Cl−/HCO transport in the ileum and colon. Although salt substitution allows favorable outcome, possible manifestations include renal impairment, intestinal inflammation, and male infertility. At least 55 mutations, of which 21 (38%) novel are reported here, cause CLD. Majority of the mutations are single nucleotide substitutions (n = 30; 55%) with 18 missense, 7 nonsense, and 5 splice-site mutations. Additional mutations are minor deletions/insertions or their combinations (n = 21; 38%), major deletions (n = 3; 5%), and a major insertion (n = 1; 2%). Distinct founder mutations appear in Finland, Poland, and Arab countries, whereas patients from other countries carry rare homozygous or compound heterozygous mutations. None of the studied SLC26A3 mutants shows significant Cl−/HCO exchange activity in vitro, and accordingly, evidence of genotype–phenotype differencies remain nonexistent. The domain interaction between SLC26A3 and the cystic fibrosis transmembrane conductance regulator (CFTR) raises a possibility of CFTR modulation in the pathogenesis of CLD. This review summarizes the current knowledge of SLC26A3 mutations and polymorphisms, and their biological and clinical relevance. Hum Mutat 32:1–8, 2011. © 2011 Wiley-Liss, Inc.
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the impact of sodium Chloride and volume depletion in the chronic kidney disease of congenital Chloride Diarrhea
Kidney International, 2008Co-Authors: Satu Wedenoja, Juha Kere, Christer Holmberg, Timo Ormala, Ulla B Berg, Stella Edstrom Halling, Hannu Jalanko, Riitta Karikoski, Pia HoglundAbstract:Congenital Chloride Diarrhea is due to mutations in the intestinal Cl − /HCO 3 − exchange (SLC26A3) which results in sodium Chloride and fluid depletion leading to hypochloremic and hypokalemic metabolic alkalosis. Although treatment with sodium and potassium Chloride offers protection from renal involvement in childhood, the long-term renal outcome remains unclear. Here we describe two cases of congenital Chloride Diarrhea-associated end-stage renal disease with transplantation. Further, we show that there is a high incidence of mild chronic kidney disease in 35 other patients with congenital Chloride Diarrhea. The main feature of the renal injury was nephrocalcinosis, without hypercalciuria or nephrolithiasis with small sized kidneys and commensurately reduced glomerular filtration rates. This suggests that Diarrhea-related sodium Chloride and volume depletion, the first signs of non-optimal salt substitution, promote urine supersaturation and crystal precipitation. The poor compliance with salt substitution along with long-lasting hypochloremic and hypokalemic metabolic alkalosis is likely to induce progressive calcification and renal failure. Both our patients developed nephrocalcinosis in the transplanted kidneys suggesting that this complication is a consequence of intestinal SLC26A3 deficiency. Interestingly, the transporter is expressed in the distal nephron but the recurrence of nephrocalcinosis in the transplanted kidney suggests that it does not play a significant renal role in this syndrome.
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long term clinical outcome in patients with congenital Chloride Diarrhea
Journal of Pediatric Gastroenterology and Nutrition, 2006Co-Authors: Satu Hihnala, Pia Hoglund, Timo Ormala, Laura Lammi, Jorma Kokkonen, Christer HolmbergAbstract:ABSTRACTObjectives:Congenital Chloride Diarrhea (CLD) is a rare, autosomal recessive disorder of intestinal Cl−/HCO3− exchange caused by mutations in the SLC26A3 gene and characterized by persistent Cl− rich Diarrhea from birth. Treatment is symptomatic and replacement therapy with NaCl and KCl has
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slc26a3 mutations in congenital Chloride Diarrhea
Human Mutation, 2002Co-Authors: Siru Makela, Juha Kere, Christer Holmberg, Pia HoglundAbstract:Congenital Chloride Diarrhea (CLD) is an autosomal recessive disorder of intestinal electrolyte absorption. It is characterized by persistent secretory Diarrhea resulting in polyhydramnios and prematurity prenatally, and dehydration, hypoelectrolytemia, hyperbilirubinemia, abdominal distention, and failure to thrive immediately after birth. CLD is caused by mutations in the solute carrier family 26, member 3 gene (SLC26A3, alias CLD or DRA), which encodes a Na+-independent Cl−/HCO3− (or OH−) exchanger. SLC26A3 is a member of the SLC26 sulfate permease/anion transporter family and it is expressed mainly in the apical brush border of intestinal epithelium. The only extraintestinal tissues showing SLC26A3 expression are eccrine sweat glands and seminal vesicles. A wide variety of different mutations in the SLC26A3 gene have been associated with CLD with no apparent evidence of phenotype–genotype correlation. The clinical course of CLD, however, is variable and may rather depend on environmental factors and compensatory mechanisms than mutations. In this report, we present a summary of all published and two novel SLC26A3 mutations and polymorphisms, and review them in the context of their functional consequences and clinical implications. Hum Mutat 20:425–438, 2002. © 2002 Wiley-Liss, Inc.
A. De La Chapelle - One of the best experts on this subject based on the ideXlab platform.
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genomic structure of the human congenital Chloride Diarrhea cld gene
Gene, 1998Co-Authors: Siru Haila, Christer Holmberg, Pia Hoglund, A. De La Chapelle, Stephen W Scherer, J R Lee, Paula Kristo, Beth Coyle, Richard C TrembathAbstract:Congenital Chloride Diarrhea (CLD) is caused by mutations in a gene which encodes an intestinal anion transporter. We report here the complete genomic organization of the human CLD gene which spans approximately 39kb, and comprises 21 exons. All exon/intron boundaries conform to the GT/AG rule. An analysis of the putative promoter region sequence shows a putative TATA box and predicts multiple transcription factor binding sites. The genomic structure was determined using DNA from several sources including multiple large-insert libaries and genomic DNA from Finnish CLD patients and controls. Exon-specific primers developed in this study will facilitate mutation screening studies of patients with the disease. Genomic sequencing of a BAC clone H_RG364P16 revealed the presence of another, highly homologous gene 3' of the CLD gene, with a similar genomic structure, recently identified as the Pendred syndrome gene (PDS).
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positional candidate genes for congenital Chloride Diarrhea suggested by high resolution physical mapping in chromosome region 7q31
Genome Research, 1996Co-Authors: Pia Hoglund, Siru Haila, Christer Holmberg, A. De La Chapelle, Stephen W Scherer, Lapchee Tsui, Eric D Green, Jean Weissenbach, Juha KereAbstract:Congenital Chloride Diarrhea affects intestinal transportation of electrolytes, resulting in potentially fatal Diarrhea. Linkage disequilibrium analyses have suggested the congenital Chloride Diarrhea gene (CLD) to lie within 0.37 cM from D7S496 in human chromosome 7q31. To clone the CLD gene, we have constructed and refined a physical map based on a 2.7-Mb YAC contig around D7S496 and identified two candidate genes. The physical positions of 4 known genes (DRA, PRKAR2B, LAMB1, DLD), 7 polymorphic repeat markers, and 13 CpG islands were established. DRA (down-regulated in adenoma) is expressed in the gut and encodes a protein with sequence homology to anion transporters, whereas PRKAR2B encodes a regulatory subunit for protein kinase A. Both genes map within 450 kb from D7S496, making them functionally and positionally relevant candidates for CLD.
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fine mapping of the congenital Chloride Diarrhea gene by linkage disequilibrium
American Journal of Human Genetics, 1995Co-Authors: Pia Hoglund, Christer Holmberg, A. De La Chapelle, Pertti Sistonen, Reijo Norio, A Dimberg, K H Gustavson, Juha KereAbstract:Congenital Chloride Diarrhea is a recessively inherited intestinal disorder affecting electrolyte transportation. The clinical presentation is a life-threatening watery Diarrhea with a high Chloride content. Recently, the congenital Chloride Diarrhea gene (CLD) was assigned to chromosome 7 by linkage in eight Finnish families. In the present study, refined mapping of CLD was performed by studying linkage and linkage disequilibrium in 24 Finnish and 4 Swedish families. Recombination mapping assigned CLD to an {approximately}10-cM region flanked by D7S515 and D7S799. Linkage disequilibrium was detected over this large genetic region, with the strongest allelic association at D7S496. Application of the Luria and Delbrueck-derived analysis allowed for a further narrowing of the CLD region to {approximately}.37 cM from the marker D7S496. Haplotype analysis placed CLD unequivocally between D7S501 and D7S692, very close to D7S496 and most likely on the distal side of D7S496. This combined analytical approach allowed highly accurate mapping of CLD, each component adding complementary and consistent mapping information. 32 refs., 4 figs., 4 tabs.
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Paternal isodisomy for chromosome 7 and normal growth and development in a patient with congenital Chloride Diarrhea
American Journal of Human Genetics, 1994Co-Authors: P. Hoeglund, A. De La Chapelle, Juha KereAbstract:Uniparental disomy (UPD) has been reported in an increasing number of patients, occasionally ascertained because of concomitant autosomal recessive disorders. In some cases, additional signs such as growth alteration, mental retardation or minor anomalies are present, suggesting an imprinting effect. For maternal chromosome 7, UPD has been described in three patients with recessive disorders. Severe growth retardation diagnosed in all these patients has been explained by the effect of imprinting of growth related genes on maternal chromosome 7. No cases of paternally derived disomy from chromosome 7 were previously known. Here we report paternal isodisomy for chromosome 7 and normal growth in a patient with a recessive disorder, congenital Chloride Diarrhea (CLD; MIM 214700). Ten informative microsatellite markers on chromosome 7 demonstrated that the proband did not have any maternal contribution to her genotype for that chromosome. Maternal and paternal alleles could not be distinguished for another 10 markers tested for chromosome 7, but the proband was always homozygous. As most uniparental paternal disomies appear to have a postzygotic origin, the primary event might have been a maternal meiotic nondisjunction. A thorough clinical evaluation with a view to additional signs of imprinted genes localized in chromosome 7 was performed. Themore » physical status and laboratory tests were normal except for a mild high-frequency sensorineural hearing loss. As the patient has normal stature, it is likely that the paternal chromosome 7 lacks the suggested maternal imprinting effect on growth. The origin of the hearing loss remains speculative.« less
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Paternal isodisomy for chromosome 7 is compatible with normal growth and development in a patient with congenital Chloride Diarrhea.
American journal of human genetics, 1994Co-Authors: Pia Hoglund, Christer Holmberg, A. De La Chapelle, Juha KereAbstract:Uniparental disomy for maternal chromosome 7 has been described in three patients with recessive disorders. Short stature in each of these patients has been explained by the effect of imprinting of growth-related genes on maternal chromosome 7. Alternatively, although less likely, all these patients may be homozygous for a rare recessive mutation. Here we report both paternal isodisomy for chromosome 7 and normal growth in a patient with a recessive disorder, congenital Chloride Diarrhea. She had inherited only paternal alleles at 10 loci and was homozygous for another 10 chromosome 7 loci studied. Her physical status and laboratory tests were normal except for a mild high-frequency sensorineural hearing loss. As the patient has normal stature, it is likely that the paternal chromosome 7 lacks the suggested maternal imprinting effect on growth. Paternal isodisomy for human chromosome 7 may have no phenotypic effect on growth.
Satu Wedenoja - One of the best experts on this subject based on the ideXlab platform.
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congenital Chloride Diarrhea and pendred syndrome case report of siblings with two rare recessive disorders of slc26 family genes
BMC Medical Genetics, 2020Co-Authors: Eva Lindberg, Juha Kere, Satu Wedenoja, Claes Moller, Agneta AnderzencarlssonAbstract:Congenital Chloride Diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic Diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness. We report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD. Familial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.
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A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR
Scientific Reports, 2017Co-Authors: Satu Wedenoja, Christer Holmberg, Pia Hoglund, Ahlam Khamaysi, Liana Shimshilashvili, Shireen Anbtawe-jomaa, Outi Elomaa, Jorma Toppari, Kristiina Aittomäki, Outi HovattaAbstract:Chloride absorption and bicarbonate excretion through exchange by the solute carrier family 26 member 3 (SLC26A3) and cystic fibrosis transmembrane conductance regulator (CFTR) are crucial for many tissues including sperm and epithelia of the male reproductive tract. Homozygous SLC26A3 mutations cause congenital Chloride Diarrhea with male subfertility, while homozygous CFTR mutations cause cystic fibrosis with male infertility. Some homozygous or heterozygous CFTR mutations only manifest as male infertility. Accordingly, we studied the influence of SLC26A3 on idiopathic infertility by sequencing exons of SLC26A3 in 283 infertile and 211 control men. A heterozygous mutation c.2062 G > C (p.Asp688His) appeared in nine (3.2%) infertile men, and additionally, in two (0.9%) control men, whose samples revealed a sperm motility defect. The p.Asp688His mutation is localized in the CFTR-interacting STAS domain of SLC26A3 and enriched in Finland, showing a significant association with male infertility in comparison with 6,572 Finnish ( P
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update on slc26a3 mutations in congenital Chloride Diarrhea
Human Mutation, 2011Co-Authors: Satu Wedenoja, Juha Kere, Christer Holmberg, Pia Hoglund, Siru Makela, Elina PekansaariAbstract:Congenital Chloride Diarrhea (CLD) is an autosomal recessive disorder with around 250 cases reported so far. Life-long secretory Diarrhea is caused by mutations in the solute carrier family 26 member 3 (SLC26A3) gene disrupting the epithelial Cl−/HCO transport in the ileum and colon. Although salt substitution allows favorable outcome, possible manifestations include renal impairment, intestinal inflammation, and male infertility. At least 55 mutations, of which 21 (38%) novel are reported here, cause CLD. Majority of the mutations are single nucleotide substitutions (n = 30; 55%) with 18 missense, 7 nonsense, and 5 splice-site mutations. Additional mutations are minor deletions/insertions or their combinations (n = 21; 38%), major deletions (n = 3; 5%), and a major insertion (n = 1; 2%). Distinct founder mutations appear in Finland, Poland, and Arab countries, whereas patients from other countries carry rare homozygous or compound heterozygous mutations. None of the studied SLC26A3 mutants shows significant Cl−/HCO exchange activity in vitro, and accordingly, evidence of genotype–phenotype differencies remain nonexistent. The domain interaction between SLC26A3 and the cystic fibrosis transmembrane conductance regulator (CFTR) raises a possibility of CFTR modulation in the pathogenesis of CLD. This review summarizes the current knowledge of SLC26A3 mutations and polymorphisms, and their biological and clinical relevance. Hum Mutat 32:1–8, 2011. © 2011 Wiley-Liss, Inc.
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congenital Chloride Diarrhea misdiagnosed as bartter syndrome
The Turkish journal of gastroenterology, 2011Co-Authors: Odul Egritas, Buket Dalgic, Satu WedenojaAbstract:Congenital Chloride Diarrhea is the most frequent secretory-type Diarrhea during the infantile period in the presence of normal intestinal mucosa. The disease has an autosomal recessive inheritance. Although approximately half of the reported cases to date are from Finland, a much higher incidence has been reported among Arabic people. The defective gene is SLC26A3, which encodes a Na-independent CL/HCO3 exchanger that is expressed primarily in the apical brush border membrane of ileal enterocytes and colonic epithelium. The disease is characterized by dehydration and hypochloremic metabolic alkalosis. Bartter syndrome, cystic fibrosis and pyloric stenosis also lead to similar electrolyte disturbances in the early neonatal period. The diagnosis of congenital Chloride Diarrhea can be confirmed by measuring the fecal concentration of Cl, which always exceeds 90 mmol/L in patients with normal water and electrolyte balance. Here, we report a patient with congenital Chloride Diarrhea misdiagnosed as Bartter syndrome until 20 months of age.
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three cases of a rare disease congenital Chloride Diarrhea summons up the variation in the clinical course and significance of early diagnosis and adequate treatment in the prevention of intellectual disability
Turkish Journal of Pediatrics, 2011Co-Authors: Figen Gurakan, Satu Wedenoja, Hasan Ozen, Gokhan Baysoy, Nuray Uslu, Fatih Ozaltin, Pia HoglundAbstract:Congenital Chloride Diarrhea (CLD) (OMIM #214700) is a rare, autosomal recessive disease that is characterized by increased Chloride loss in stool. As a result of electrolyte loss, surviving patients might have some complications, one of them being mental retardation. Here, we present three new Turkish patients with new mutations in the SLC26A3 gene. Although the clinical picture of the patients might be similar, consequences of the disease and complications might differ greatly among patients. Pediatricians should be aware of CLD as a potentially fatal or disabling disease if untreated. History of polyhydramnios, watery Diarrhea, failure to thrive, poor growth, soiling, metabolic alkalosis and hypokalemia/hypochloremia should be an alarming set of findings for the diagnosis. Salt substitution therapy started early in life prevents early complications, allows normal growth and development, and favors good long-term prognosis.