Whole-Exome Sequencing Identified Novel CLMP Mutations in a Family With Congenital Short Bowel Syndrome Presenting Differently in Two Probands

Abstract

Congenital short bowel syndrome (CSBS) is a rare condition characterized by an inborn shortening of bowel length with loss of intestinal functions, which often combines malrotation. CXADR-like membrane protein (CLMP) and filamin A (FLNA) gene mutations are the two major causes of this inherited defect. We presented two siblings with the older brother suffering from a laparotomy for bowel obstruction due to malrotation on the 17th day after birth. The younger sister encountered a laparotomy for lactobezoar at 6 months old. CSBS was diagnosed by measurement of the bowel length during the operations. Compound heterozygous CLMP mutations with the paternal allele harboring a long deletion across exon 3–5 and the maternal allele bearing a non-sense mutation of exon 3 (c.235C > T, p.Q79∗) were identified in both cases. They are the first reported familial CSBS caused by novel CLMP mutations in Taiwan.

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“…The CLMP gene, which encodes the Coxsackie-and adenovirus receptor-like membrane protein, has been implicated in various physiological and pathological processes. It is known to be associated with congenital short-bowel syndrome (CSBS) 64,65,66 . The CLMP gene plays a crucial role in cell adhesion and is essential for maintaining normal intestinal homeostasis and development by stabilizing the gut vascular barrier positioned between endothelial and epithelial cells within the junctional complex..…”

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“…In contrast, it is known that TM4SF can interact with integrin to affect various cellular functions and mediate signal transduction events that are associated with numerous physiological functions, such as cell development, activation, growth and motility [53]. The mechanisms by which TM4SF regulates in GC metastasis remains to be shown.…”

The IgSF Cell Adhesion Protein CLMP and Congenital Short Bowel Syndrome (CSBS)

“…However, missense, nonsense, splicing mutations and larger deletions in the region of CLMP encoding the extracellular domain have been found in association with CSBS ( Figure 1 ). The majority of these are nonsense mutations and splicing errors of the premature mRNA, which result in a premature stop of the CLMP polypeptide and eliminate its cell surface anchorage [ 4 , 5 , 6 , 10 , 11 , 12 ]. Whether these truncated forms of CLMP are secreted, intracellularly degraded or whether the process of nonsense-mediated mRNA decay eliminates these transcripts with a premature stop is not yet known [ 18 , 19 ].…”

“…To date, no CSBS-linked mutations have been found in the cytoplasmic segment. The larger deletions in the CLMP gene—deletions in exons 3 to 5 with sizes of 1629, 4227, or 12,483 bp [ 11 , 12 , 13 , 14 ] and a deletion in intron 1 and exon 2 [ 11 ]—are unlikely to produce protein fragments. In addition, mutations that affect the splicing of the pre-mRNA are found in several introns [ 4 , 5 , 10 , 11 , 13 ].…”

“…Following the work of Van der Werf et al, there have been further case reports of CSBS patients with mutations in the human CLMP gene (nonsense and missense mutations, splicing errors and deletions of larger parts of the gene) [ 4 , 5 , 6 , 10 , 12 , 13 , 14 ]. The positions of these CSBS-associated mutations in relation to the structural domains of CLMP are shown in Figure 1 .…”