Variants of the ACTG2 gene correlate with degree of severity and presence of megacystis in chronic intestinal pseudo-obstruction

Abstract

Chronic intestinal pseudo-obstruction (CIPO) syndromes are heterogeneous gastrointestinal disorders, caused by either neuropathy or myopathy, resulting in compromised peristalsis and intestinal obstruction. CIPO can have a profound impact on quality of life, leading the most severely affected individuals to life-long parenteral nutrition and urinary catheterization. To search for disease causing gene(s), we performed the whole exome sequencing (WES) in both eight sporadic and two familial cases, followed by targeted sequencing in additional CIPO patients. After identifying a heterozygous missense variant in the ACTG2 gene in one of 10 patients undergone WES, targeted Sanger sequencing of this gene allowed to detect heterozygous missense variants in 9 of 23 further patients with either megacystis-microcolon-intestinal hypoperistalsis syndrome or intestinal pseudo-obstruction. Variants thus identified, one of which still unreported, affect highly conserved regions of the ACTG2 gene that encodes a protein crucial for correct enteric muscle contraction. These findings provided evidence for a correlation between the clinical phenotype and genotype at the ACTG2 locus, a first step to improve the diagnosis and prognosis of these severe conditions.

Figure 1

Representive histopathological pictures of the colon obtained from patient S9 (see Table 1). (a) Note a clearly detectable change in the thickness and structural organization of the muscularis propria of the distal (right) and proximal (left) colon; notably the muscle thickness in the distal colon exceeds that of the proximal colon. Hematoxylin and eosin staining. Original magnification 50x for both right and left pictures. The lower panel shows a significant reduction of the smooth muscle actin (SMA) immunolabeling in the distal colon (right); SMA immunolabeling was even absent in the most affected proximal colon (left). Original magnification was 50 × for both right and left pictures. (b) MAP-2 immunohistochemical staining (400 ×) shows the presence of giant ganglia. A full color version of this figure is available at the European Journal of Human Genetics journal online.