Whole-Exome Sequencing Identifies the 6q12-q16 Linkage Region and a Candidate Gene, TTK, for Pulmonary Nontuberculous Mycobacterial Disease

Abstract

The TTK gene encodes a protein kinase that is essential for mitotic checkpoints and the DNA damage response. TTK and other genetic loci identified in our study may contribute to the increased susceptibility to NTM infection and its progression to pulmonary disease.

The Rise of Non-Tuberculosis Mycobacterial Lung Disease

“…Described as "Lady Windermere syndrome" these patients often have a distinct physical phenotype of slender build, pectus excavatum or scoliosis and mitral valve prolapse, though notably they have no known immune dysfunction (16,19,28). Recently identified genetic defects that could contribute to susceptibility in these "Lady Windemere" patients include cystic fibrosis transmembrane conductance regulator gene (CFTR) related mutations, ciliary function, and other connective tissue related genetic defects as well as the DNA damage response protein TTK defects (22,(29)(30)(31). Finally, gastro-esophageal reflux disease (GORD), vitamin D deficiency, rheumatoid arthritis (26,32,33) and low body mass index (BMI) are art risk of NTM lung disease (34).…”

Update in Tuberculosis and Nontuberculous Mycobacteria 2017

“…Familial clustering of pulmonary NTM disease is rare but has been reported in carefully-performed studies (45). Applying whole-exome sequencing technology to 9 families with pulmonary NTM, and then including a further 57 sporadic cases (where the unaffected family members acted as controls for all tested cases), Chen and colleagues identified a 20-cM (20,000 kilobase) region on chromosome 6q12-6q16 with a HLOD (heterogeneity logarithm of the odds) score of 3.9 (>3.3 was regarded as indicating linkage) (46). This fitted best under a recessive disease model with 100% penetrance and a AJRCCM Update in Tuberculosis 2017 risk allele frequency of 5%.…”

“…Using gene-level linkage analysis, they determined the genes potentially driving the linkage signals. TTK protein kinase (TTK) gene, which has a role in regulating proper chromosomal alignment and hence controlling DNA damage and repair, was most strongly associated (46). It remains to be seen whether this proposed mechanism (where aberrant TTK gene function could result in failure of local innate pulmonary immunity and so allow environmental NTM to colonise, infect and ultimately cause disease) is relevant to many NTM patients with unexplained disease, or if it is a phenomenon arising in patients selected by their atypical -and hence who were studied.…”

Pulmonary non-tuberculous mycobacterial infections: current state and future management

“…Cystic fibrosis (CF) is an autosomal recessive disease, caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene predominantly found in Caucasian populations, is characterized by CFTR dysfunction [61]. The CF patients have decreased secretion of chloride and bicarbonate across the CFTR channel and increased absorption of sodium through the epithelial sodium channel, • Bronchiectasis [53][54][55][56] • Post TB infection [57][58][59][60] • Cystic fibrosis [61][62][63][64][65][66] • ABPA [67][68][69][70][71][72][73] • Impaired mucociliary clearance [74][75][76][77] b) Genetic defects • Genetic defects in genes related with immune response, CFTR, cilia, and connective tissue [74,[78][79][80][81][82][83]…”

“…Many of the patients had simultaneous defects in various genes, comprising of different categories [79]. Evidence of genetic linkage on chromosome 6q12-q16 with PNTM and the identification of TTK as a candidate gene for PNTM have been found in PNTM patients [80]. Also, haplotypic association with PNTM has been reported [81].…”