Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea

Höglund, Pia; Sormaala, Markus J.; Haila, Siru; Socha, Jerzy; Rajaram, Usha; Scheurlen, Wolfram; Sinaasappel, M.; Jonge, Hugo de; Holmberg, Christer; Yoshikawa, Hideto; Kere, Juha

doi:10.1002/humu.1179

Cited by 28 publications

(20 citation statements)

References 27 publications

(32 reference statements)

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“…Such sequence alterations have been previously described for other genes coding for comparatively large protein molecules, exhibiting channel (SLC26A3 or CLD gene, involved in congenital chloride diarrhea) or receptor functions (LDL receptor gene involved in atherosclerosis) [Heath et al, 2001;Hoglund et al, 2001]. In the case of factor VIII, several gross complex rearrangements have been already reported for the gene [http://europium.csc.mrc.ac.uk ; Kazazian et al, 1988].…”

Section: Discussionmentioning

confidence: 77%

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

Bogdanova

Markoff²,

Pollmann

et al. 2002

Hum. Mutat.

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Hemophilia A is a common X-linked bleeding disorder caused by various types of mutations in the factor VIII gene F8C. The most common intron 22-inversion is responsible for about 40% of the severe hemophilia A cases while large deletions, point mutations and small (less than 100 bp) deletions or insertions are responsible for the disease in the rest of patients. We report on nine novel (6 deletions, two indels and one partial duplication) and five recurrent small rearrangements identified in 15 German patients with severe hemophilia A, negative for the intron 22-inversion. c.2208-2214delTTATTAC/c.2207-2215insCTCTT and c.4665-4678del/c.4664-4678insAAGGAA identified in the present study are the first small indels described in the factor VIII gene. Our analyses suggest that the prevalence of this type of mutations (predominantly located in exon 14) among patients with severe phenotype and negative for the common intron 22-inversion, is about 30%. The correlation between these molecular defects and formation of factor VIII inhibitors as well as the parental origin of the de novo mutations are evaluated. Finally we show that denaturing HPLC (DHPLC) and classic heteroduplex analysis (HA) are able to detect these sequence alterations on 100% and could be preferred as a screening approach when analysing for mutations in factor VIII in severely affected patients.

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Section: Discussionmentioning

confidence: 77%

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

Bogdanova

Markoff²,

Pollmann

et al. 2002

Hum. Mutat.

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“…(5,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Mouse studies have revealed additional roles for these Slc26 proteins in mammalian physiology: deafness, goiter, and acidosis (Slc26a4, pendrin) (42-44), cochlear motor protein (Slc26a5, prestin) (45)(46)(47), proximal tubule NaCl absorption, nephrolithiasis, and intestinal HCO 3 Ϫ secretion (Slc26a6, Pat-1, CFEX) (8, 48 -52), sperm motility (Slc26a8, Tat-1) (53), and gastric acid secretion (Slc26a9) (14).…”

Section: Discussionmentioning

confidence: 99%

Slc26a9 Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain

Chang

Plata

Sinđić

et al. 2009

Journal of Biological Chemistry

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SLC26 proteins function as anion exchangers, channels, and sensors. Previous cellular studies have shown that Slc26a3 and Slc26a6 interact with the R-region of the cystic fibrosis transmembrane conductance regulator (CFTR), (R)CFTR, via theSlc26 genes and proteins have attracted the attention of physiologists and geneticists. Why? Slc26a1 (Sat-1) was characterized as a Na ϩ -independent SO 4 2Ϫ transporter (1). Given the transport characteristics of the founding member of the gene family, Slc26 proteins were assumed to be sulfate transporters. Disease phenotypes, clone characterization, and family additions demonstrate that the Slc26 proteins are anion transporters or channels (2-4). These proteins have varied tissue expression patterns. At one extreme, Slc26a5 in mammals is found in the hair cells of the inner ear (5), whereas Slc26a2 (DTDST) is virtually ubiquitous in epithelial tissues (2).Several Slc26 proteins are found in the epithelia of the lung, intestine, stomach, pancreas, and kidney, usually in apical membranes. Interestingly these are also tissues and membranes in which the cystic fibrosis transmembrane conductance regulator (CFTR) 5 has been found functionally or by immunohistochemistry. Ko and co-workers (6 -8) examined the distribution of Slc26a3 and Slc26a6 in HCO 3 Ϫ secretory epithelia, and asked if an interaction might occur between these Slc26 proteins and CFTR. In particular, these studies indicate that in expression systems, there is a reciprocal-stimulatory interaction of the STAS (sulfate transporter anti-sigma) domains of Slc26a3 and Slc26a6 with the regulatory region (R-region) of CFTR. These investigators hypothesized that this stimulatory interaction could account for the differences in pancreatic insufficiency and sufficiency observed in cystic fibrosis patients. Nevertheless, knock-out Slc26a6 mouse studies reveal more complicated cell and tissue physiology (see "Discussion").Slc26a9 has been reported to be a Cl Ϫ -HCO 3 Ϫ exchanger (9, 10) or a large Cl Ϫ conductance (3,11,12). Loriol and co-workers (12) indicated that SLC26A9 has a Cl Ϫ conductance that may be stimulated by HCO 3 Ϫ . Two other groups have indicated that the Cl Ϫ conductance is not affected by the presence of HCO 3 Ϫ (10, 11). We have recently demonstrated that Slc26a9 functions as both an electrogenic nCl Ϫ -HCO 3 Ϫ exchanger and a Cl Ϫ channel (10). Dorwart and colleagues (11) found that WNK kinases inhibited the SLC26A9 Cl Ϫ conductance but that this effect was independent of kinase activity. One group has a preliminary report indicating that WNK3 decreased Cl Ϫ uptake,

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“…More than 50 different mutations have been reported with founder mutations in specific populations (eg, Finnish and Arab). 84,85 Management of congenital chloride diarrhea revolves around preventing dehydration and alkalosis through enteral fluid and electrolyte supplementation. Oral administration of butyrate was found to reduce diarrheal output, although subsequent studies have reported more equivocal results.…”

Section: Disorders Of Epithelial Nutrient/electrolyte Transportmentioning

confidence: 99%

Advances in Evaluation of Chronic Diarrhea in Infants

et al. 2018

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Diarrhea is common in infants (children less than 2 years of age), usually acute, and, if chronic, commonly caused by allergies and occasionally by infectious agents. Congenital diarrheas and enteropathies (CODEs) are rare causes of devastating chronic diarrhea in infants. Evaluation of CODEs is a lengthy process and infrequently leads to a clear diagnosis. However, genomic analyses and the development of model systems have increased our understanding of CODE pathogenesis. With these advances, a new diagnostic approach is needed. We propose a revised approach to determine causes of diarrhea in infants, including CODEs, based on stool analysis, histologic features, responses to dietary modifications, and genetic tests. After exclusion of common causes of diarrhea in infants, the evaluation proceeds through analyses of stool characteristics (watery, fatty, or bloody) and histologic features, such as the villus to crypt ratio in intestinal biopsies. Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt ratios and morphology. Whole-exome and genome sequencing in the early stages of evaluation can reduce the time required for a definitive diagnosis of CODEs, or lead to identification of new variants associated with these enteropathies. The functional effects of gene mutations can be analyzed in model systems such as enteroids or induced pluripotent stem cells and are facilitated by recent advances in gene editing procedures. Characterization and investigation of new CODE disorders will improve management of patients and advance our understanding of epithelial cells and other cells in the intestinal mucosa.

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Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea

Cited by 28 publications

References 27 publications

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

Slc26a9 Is Inhibited by the R-region of the Cystic Fibrosis Transmembrane Conductance Regulator via the STAS Domain

Advances in Evaluation of Chronic Diarrhea in Infants

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