Association of the CLCA1 p.S357N Variant With Meconium Ileus in European Patients With Cystic Fibrosis

Abstract

In Cftr-/- mice that mostly die because of intestinal obstruction, intestinal expression of Clca3 is decreased, whereas upregulation of Clca3 results in amelioration of intestinal disease. The aim of the study was to investigate whether the p.S357N variant in CLCA1, the human orthologue of Clca3, acts as a modifier gene in a cohort of 682 European patients with cystic fibrosis (CF)-99 patients with meconium ileus. The 357SS genotype was significantly overrepresented in both patients with meconium ileus and also with a severe CFTR genotype (P = 0.009) and in p.F508del homozygotes (P = 0.002). This suggests that CLCA1 has similar important functions in CF-related intestinal obstruction in humans as in Cftr-/- mice.

Self-cleavage of Human CLCA1 Protein by a Novel Internal Metalloprotease Domain Controls Calcium-activated Chloride Channel Activation

“…Fatal intestinal disease found in CFTR-deficient mice, however, is corrected by overexpression of native mouse CLCA3 (an orthologue of human CLCA1) (17). Consistent with this observation, a mutation in the CLCA1 gene is found in a subset of CF patients with more severe intestinal disease (18). These studies indicate that CLCA1 may function to alleviate CFTR deficiency symptoms by increasing endogenous CaCC activity and compensating for defective CFTR-mediated chloride transport.…”

Intestinal Obstruction Syndromes in Cystic Fibrosis: Meconium Ileus, Distal Intestinal Obstruction Syndrome, and Constipation

“…The recent consensus guidelines issued by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) CF Working Group define DIOS as an acute, complete or incomplete, fecal obstruction in the ileocecum, whereas constipation is defined as gradual fecal impaction of the total colon (Tables 1 and 2) [10]. Using these definitions, both the incidence (2.2–6.2 episodes per 1000 patient-years) and lifetime prevalence (7–8%) of DIOS in childhood is low [9, 11•, 12, 13]. Two studies report that DIOS incidence and lifetime prevalence increase as patients become older [12, 13]; indeed, incidence (23.3 episodes per 1000 patient-years) and lifetime prevalence (14–16%) are higher in adult patients [12–14].…”

“…Reports on lifetime prevalence of constipation are scarce; only two studies for pediatric patients (published in 1986 and 2010) [9, 13] and one for adult patients (published in 1986) [13] are available. They show that constipation is very common in both pediatric (lifetime prevalence 26–47%) and adult (lifetime prevalence 42%) CF patients [9, 13].…”

Variation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis

“…Rozmahel and colleagues suggested that Clca3 may reduce mucin release from goblet cells, given the observation of increased goblet cell size, thereby reducing luminal mucus content and intestinal obstruction in the CF mice [31]. Evidence of association between MI and the p.Ser357Asn variant in CLCA1 , the human ortholog of the murine Clca3 , in 682 European CF subjects suggests that this goblet cell marker may also contribute to intestinal obstruction in humans [52]. Thus, alteration of mucus content in the CF intestine, either by reduction in goblet cell numbers or down-regulation of mucus release, appears to affect the rate of intestinal obstruction.…”