Abstract
Congenital diarrheal disorders (CDD) comprise > 50 monogenic entities featuring chronic diarrhea of early-onset, including defects in nutrient and electrolyte absorption, enterocyte polarization, enteroendocrine cell differentiation, and epithelial integrity. Diarrhea is also a predominant symptom in many immunodeficiencies, congenital disorders of glycosylation, and in some defects of the vesicular sorting and transporting machinery. We set out to identify the etiology of an intractable diarrhea in 2 consanguineous families by whole-exome sequencing, and identified two novel AP1S1 mutations, c.269T>C (p.Leu90Pro) and c.346G>A (p.Glu116Lys). AP1S1 encodes the small subunit of the adaptor protein 1 complex (AP-1), which plays roles in clathrin coat-assembly and trafficking between trans-Golgi network, endosomes and the plasma membrane. An AP1S1 knock-out (KO) of a CaCo2 intestinal cell line was generated to characterize intestinal AP1S1 deficiency as well as identified mutations by stable expression in KO background. Morphology and prototype transporter protein distribution were comparable between parental and KO cells. We observed altered localization of tight-junction proteins ZO-1 and claudin 3, decreased transepithelial electrical resistance and an increased dextran permeability of the CaCo2-AP1S1-KO monolayer. In addition, lumen formation in 3D cultures of these cells was abnormal. Re-expression of wild-type AP1S1 in CaCo2-AP1S1-KO cells reverted these abnormalities, while expression of AP1S1 containing either missense mutation did not. Our data indicate that loss of AP1S1 function causes an intestinal epithelial barrier defect, and that AP1S1 mutations can cause a non-syndromic form of congenital diarrhea, whereas 2 reported truncating AP1S1 mutations caused MEDNIK syndrome, characterized by mental retardation, enteropathy, deafness, neuropathy, ichthyosis, and keratodermia.
Highlights
Congenital diarrheal disorders (CDD) generally result from specific genetic defects inherited as autosomal recessive traits, with a severe clinical presentation
MEDNIK syndrome, known as “syndrome de Kamouraska”, is a genetic disorder that is caused by mutations in adaptor related protein complex 1 subunit sigma 1 (AP1S1) and beta 1 (AP1B1) genes (Alsaif et al 2019; Martinelli and Dionisi-Vici 2014)
Three patients with congenital diarrhea from two unrelated families were identified with AP1S1 variants by whole-exome sequencing (WES)
Summary
Congenital diarrheal disorders (CDD) generally result from specific genetic defects inherited as autosomal recessive traits, with a severe clinical presentation. MEDNIK syndrome, known as “syndrome de Kamouraska” (syndrome from Kamouraska), is a genetic disorder that is caused by mutations in adaptor related protein complex 1 subunit sigma 1 (AP1S1) and beta 1 (AP1B1) genes (Alsaif et al 2019; Martinelli and Dionisi-Vici 2014). Diagnostic procedures for these disorders and therapeutic pathways for the care of affected patients have only recently been suggested (Thiagarajah et al 2018). This has led to the continued identification of new congenital diarrheas and enteropathies (O’Connell et al 2018; Ozen et al 2017; van Rijn et al 2018)
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