ClinVar Genomic variation as it relates to human health

In a girl (family 1) with gastrointestinal defects and immunodeficiency syndrome-1 (GIDID1; 243150), who presented almost immediately after birth with bloody diarrhea and who also had lymphopenia and hypogammaglobulinemia, Avitzur et al. (2014) identified compound heterozygosity for 2 mutations in the TTC7A gene: a c.211G-A transition (rs147914967) in exon 2 of the TTC7A gene, resulting in a glu71-to-lys (E71K) substitution in the highly conserved alpha-helical region, and a c.1944C-T transition in exon 14, resulting in a gln526-to-ter (Q526X; 609332.0015) substitution. Her unaffected Caucasian mother and Sudanese father were each heterozygous for 1 of the mutations, neither of which was found in the NCBI or 1000 Genomes Project databases; the E71K mutation was detected in 1 of 13,006 control alleles in the NHLBI Exome Sequencing Project database, whereas the Q526X mutation was not found in that database. Colonoscopy showed chronic inflammation with severe friability, exfoliative mucosal changes, and sloughed mucosa within the lumen. Pathologic analysis of duodenal biopsies showed villous atrophy, and the duodenum and colon showed glandular dropout with crypt apoptosis and exploding crypts; the severity of the epithelial injury was reminiscent of that seen in acute graft-versus-host disease and intestine allograft rejection. Overexpression of E71K- and Q526X-mutant TTC7A in Caco2 cells demonstrated cytoplasmic accumulation of TTC7A in addition to disrupted cortical actin staining, suggestive of adhesion defects or loss of cellular polarity. Tandem mass spectrometry of proteins from HEK293T cells expressing TTC7A revealed reduced coimmunoprecipitation of PI4KIII-alpha (PI4KA; 600286) fragments with the E71K or Q526X mutants compared to wildtype TTC7A. The patient died of respiratory failure at 11 months of age; autopsy showed no evidence of bowel atresia, but confirmed widespread severe apoptotic enterocolitis. In 13 affected individuals from a large consanguineous family with early-onset inflammatory bowel disease and combined immunodeficiency, Lemoine et al. (2014) identified homozygosity for the E71K substitution in the TTC7A gene. All parents who were tested were heterozygous for the mutation, and all heterozygotes were asymptomatic. TTC7A protein was not detectable in patient T lymphoblasts by Western blot analysis. However, patient T lymphocytes exhibited multiple alterations related to cytoskeletal remodeling, including increased spreading, adhesion, and reduced capacity for migration in response to chemoattractants; in addition, patient T cells had preserved proliferation in response to mitogens, but markedly impaired proliferation to antigens. Lemoine et al. (2014) observed increased ROCK (601702) activity in patient cells, and demonstrated that inhibition of ROCK activity could rescue the TTC7A-deficient T-cell phenotype. A 3D epithelial 'organoid' culture generated from a patient rectal biopsy specimen showed disturbed architecture with condensed cell aggregates and an aberrant, partially inverted polarity; inhibition of ROCK resulted in lumen expansion and correction of polarity in the gut 'organoids.' (less)