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Identification of a rare LAMB4 variant associated with familial diverticulitis through exome sequencing
- Publication Year :
- 2017
- Publisher :
- Oxford University Press, 2017.
-
Abstract
- Diverticulitis is a chronic disease of the colon in which diverticuli, or outpouching through the colonic wall, become inflamed. Although recent observations suggest that genetic factors may play a significant role in diverticulitis, few genes have yet been implicated in disease pathogenesis and familial cases are uncommon. Here, we report results of whole exome sequencing performed on members from a single multi-generational family with early onset diverticulitis in order to identify a genetic component of the disease. We identified a rare single nucleotide variant in the laminin β 4 gene (LAMB4) that segregated with disease in a dominant pattern and causes a damaging missense substitution (D435N). Targeted sequencing of LAMB4 in 148 non-familial and unrelated sporadic diverticulitis patients identified two additional rare variants in the gene. Immunohistochemistry indicated that LAMB4 localizes to the myenteric plexus of colonic tissue and patients harboring LAMB4 variants exhibited reduced LAMB4 protein levels relative to controls. Laminins are constituents of the extracellular matrix and play a major role in regulating the development and function of the enteric nervous system. Reduced LAMB4 levels may therefore alter innervation and morphology of the enteric nervous system, which may contribute to colonic dysmotility associated with diverticulitis.
- Subjects :
- 0301 basic medicine
Adult
Male
Pathology
medicine.medical_specialty
Disease
Polymorphism, Single Nucleotide
03 medical and health sciences
Laminin
Exome Sequencing
Genetics
medicine
Missense mutation
Humans
Exome
Genetic Predisposition to Disease
Molecular Biology
Gene
Genetics (clinical)
Exome sequencing
Myenteric plexus
Diverticulitis
biology
General Medicine
Articles
Sequence Analysis, DNA
Middle Aged
medicine.disease
Pedigree
030104 developmental biology
biology.protein
Enteric nervous system
Female
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....09923fea22d8c66923b2d507fcc43522