MYO5B,STX3, andSTXBP2mutations reveal a common disease mechanism that unifies a subset of congenital diarrheal disorders: A mutation update

Abstract

Microvillus inclusion disease (MVID) is a rare but fatal autosomal recessive congenital diarrheal disorder caused by MYO5B mutations. In 2013, we launched an open‐access registry for MVID patients and their MYO5B mutations (www.mvid-central.org). Since then, additional unique MYO5B mutations have been identified in MVID patients, but also in non‐MVID patients. Animal models have been generated that formally prove the causality between MYO5B and MVID. Importantly, mutations in two other genes, STXBP2 and STX3, have since been associated with variants of MVID, shedding new light on the pathogenesis of this congenital diarrheal disorder. Here, we review these additional genes and their mutations. Furthermore, we discuss recent data from cell studies that indicate that the three genes are functionally linked and, therefore, may constitute a common disease mechanism that unifies a subset of phenotypically linked congenital diarrheal disorders. We present new data based on patient material to support this. To congregate existing and future information on MVID geno‐/phenotypes, we have updated and expanded the MVID registry to include all currently known MVID‐associated gene mutations, their demonstrated or predicted functional consequences, and associated clinical information.

A V0-ATPase-dependent apical trafficking pathway maintains the polarity of the intestinal absorptive membrane

“…Notably, enterocytes of patients with MVID also display similar polarity defects to those observed upon V0/vha-1(RNAi), such as the basolateral appearance of microvilli-specific proteins (Wiegerinck et al, 2014) and PAR polarity module components (Michaux et al, 2016) as well as the cytoplasmic displacement of trafficking proteins (i.e. STX3, the SNARE family component SNAP23 and cellubrevin; Dhekne et al, 2018). Finally, MVID has also been associated with enlarged lysosomes displaying a heterogeneous content and with the accumulation of cytoplasmic translucent vesicles (Iancu et al, 2007;Vogel et al, 2016) as well as the specific disorganization of Rab11 + apical recycling endosomes (Vogel et al, 2017a;Talmon et al, 2012), which we also found in V0-ATPase knocked-down worms (Fig.…”

Two cases of microvillous inclusion disease caused by novel mutations in MYO5B gene

“…All the other mutations were found in single MVID patients. Finally, 62 different mutations (including the c.1979C>T that is peculiar to Navajos) were found in the MVID patients studied so far . Several of these mutations have a clear pathogenic effect (ie, nonsense, splicing, or frameshift), while 24 were missense.…”

“…Finally, 62 different mutations (including the c.1979C>T that is peculiar to Navajos) were found in the MVID patients studied so far. 18 Several of these mutations have a clear pathogenic effect (ie, nonsense, splicing, or frameshift), while 24 were missense. We revised 15 of them by using several bioinformatic tools 20 and predicted the pathogenicity (Table S1) in all cases with the exception of the c.1856C>T mutation, which was found in a Dutch patient with MVID that had two other pathogenic mutations (Table 1).…”

“…A founder mutation was identified among Navajos while about 60 different mutations were described so far in patients from other ethnic groups indicating the strong genetic heterogeneity of the disease. These findings were reviewed in the excellent papers by van der Velde and Dhekne . More recently, the Syntaxin 3 gene was reported as responsible for an MVID variant …”

“…These findings were reviewed in the excellent papers by van der Velde 17 and Dhekne. 18 More recently, the Syntaxin 3 gene was reported as responsible for an MVID variant. 19 In the present paper, we describe two cases of MVID bearing novel MYO5B mutations and revise the pathogenic role of MYO5B mutations described in MVID patients so far.…”