Update on SLC26A3 mutations in congenital chloride diarrhea

Abstract

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 À /HCO 3 À 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 5 30; 55%) with 18 missense, 7 nonsense, and 5 splice-site mutations. Additional mutations are minor deletions/insertions or their combinations (n 5 21; 38%), major deletions (n 5 3; 5%), and a major insertion (n 5 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

Congenital Chloride Losing Diarrhea

“…The disease is particularly frequent in: Kuwait with an incidence of 1/3200 due to a high prevalence of consanguinity marriages in these countries, Saudi Arabia , it was 1st described in 1981 with an incidence of 1/5000, Finland with an Incidence of 1/30,000-40,000, and Poland with an Incidence of 1/200,000 ( Figure 1) [6,9].…”

“…It is a rare autosomal recessive disorder caused by mutations in the CLD gene called the solute carrier family 26 member 3 gene (SLC26A3 alias DRA), mapped to chromosome 7q31 [6,12]. It encodes for an apical epithelial Cl−/HCO 3 −exchanger, the intestinal loss of which causes profuse Cl−-rich diarrhea [10,13].…”

“…SLC26A3 encodes for a trans-membrane protein, which is an apical epithelial (Cl⁄HCO 3 ) exchanger [4,6,11,14,17,18]. The basic defect of CLD is loss of the SLC26A3-mediated transport in the surface epithelium of the ileum and colon [19][20][21][22][23] (Figure 3).…”

“…Affected fetuses develop secretory "urine like" diarrhea [27] (Figure 7) in utero resulting in distended bowel loops and polyhydramnios which leads to premature birth and lack of meconium [6,17]. These abnormalities are visible in ultrasonic investigation Figure 4, even at the end of the second trimester [28,29].…”

“…In 1945, Holmberg et al and wedejoja et al, [5,6] published reports of two patients presenting with a new syndrome, characterized by watery diarrhea, high content of chloride in the stools, and metabolic alkalosis. The disease was named metabolic alkalosis with diarrhea, or congenital chloridorrhea but when the primary pathology was understood to involve the transport of chloride, in the distal ileum and colon, the disease was renamed as Congenital Chloride Diarrhea (CCD) or Chloride Losing Diarrhea (CLD) [7,8].…”