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Hum Mol Genet. 2017 Aug 15;26(16):3212-3220. doi: 10.1093/hmg/ddx204.

Identification of a rare LAMB4 variant associated with familial diverticulitis through exome sequencing.

Author information

1
Department of Biochemistry and Molecular Biology.
2
Department of Surgery, Division of Colon and Rectal Surgery.
3
Division of Anatomical Pathology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
4
Department of Medical Genetics and Molecular Biochemistry, Temple University College of Medicine, Philadelphia, PA 19140, USA.

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.

PMID:
28595269
PMCID:
PMC6251658
DOI:
10.1093/hmg/ddx204
[Indexed for MEDLINE]
Free PMC Article

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