MYO5B – Microvillus Inclusion Disease

Microvillus inclusion disease (MVID) is a severe autosomal recessive enteropathy characterized by life-threatening secretory diarrhea, malabsorption, and failure to thrive. Histologically, affected enterocytes display loss of apical microvilli and cytoplasmic inclusions lined by microvilli. Biallelic loss-of-function variants in the MYO5B gene, encoding the motor protein myosin Vb, underlie the pathogenesis of MVID, disrupting apical trafficking and cell polarity in intestinal epithelial cells.

Extensive genetic evidence supports a definitive gene-disease relationship. Over 250 unrelated probands with biallelic MYO5B variants have been reported across diverse populations, including a cluster of seven Navajo patients homozygous for c.1979C>T (p.Pro660Leu) with expected parental segregation (PMID:19006234). Compound heterozygous and homozygous nonsense, missense, splice-site, and frameshift variants have been identified in multiple case series, with systematic reviews enumerating 323 patients with congenital diarrheal disorders, many attributed to MYO5B deficiency (PMID:33976085).

The variant spectrum encompasses nonsense (e.g., c.445C>T (p.Gln149Ter)), splice-site (e.g., c.2090+3A>T), missense, and frameshift alleles. A representative frameshift, c.1462del (p.Ile488LeufsTer93), was discovered homozygously in an infant with classic MVID presentation and failure to thrive (PMID:31559144). Parental segregation analyses and recurrence of founder alleles confirm autosomal recessive inheritance.

Functional assays demonstrate that MYO5B loss-of-function recapitulates MVID cellular pathology. MYO5B knock-down in CaCo-2 cells induces microvillus inclusion formation, loss of apical microvilli, and mislocalization of apical transporters (PMID:24138727). Animal models corroborate enterocyte polarity defects. Rescue experiments with lysophosphatidic acid receptor activation and Notch inhibition partially restore apical sodium and water transporters, highlighting therapeutic avenues (PMID:35660026).

Prenatal findings further substantiate disease onset in utero. Third-trimester ultrasound reveals dilated bowel loops and polyhydramnios in up to 60% of MVID cases, correlating with postnatal early-onset diarrhea and MYO5B loss-of-function variants (PMID:35893420). These observations support the use of prenatal genetic testing following suggestive sonographic abnormalities.

ClinGen classification: Definitive. MYO5B exhibits robust genetic and experimental concordance with MVID. Early molecular diagnosis informs neonatal management, genetic counseling, and prenatal planning. Key Take-home: Genetic testing for MYO5B should be integrated into the diagnostic workflow for congenital secretory diarrhea and prenatal cases with fetal bowel abnormalities.

References

• American journal of medical genetics. Part A | 2008 | Navajo microvillous inclusion disease is due to a mutation in MYO5B. PMID:19006234
• Journal of pediatric gastroenterology and nutrition | 2019 | Congenital diarrhea in a newborn infant: A case report. PMID:31559144
• Journal of clinical medicine | 2022 | Fetal Bowel Abnormalities Suspected by Ultrasonography in Microvillus Inclusion Disease: Prevalence and Clinical Significance. PMID:35893420
• Traffic (Copenhagen, Denmark) | 2014 | Microvillus inclusion disease: loss of Myosin vb disrupts intracellular traffic and cell polarity. PMID:24138727
• Cellular and molecular gastroenterology and hepatology | 2022 | Altered MYO5B Function Underlies Microvillus Inclusion Disease: Opportunities for Intervention at a Cellular Level. PMID:35660026
• Journal of pediatric gastroenterology and nutrition | 2021 | Genetic Enteropathies Linked to Epithelial Structural Abnormalities and Enteroendocrine Deficiency: A Systematic Review. PMID:33976085

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