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Defects in Lymphocyte Telomere Homeostasis Contribute to Cellular Immune phenotype in Cartilage-Hair Hypoplasia

Posted January 25, 2017 | Publications

Aubert G, Strauss KA, Lansdorp PM & Rider NL. Journal of Allergy and Clinical Immunology, in press.


Mutations in the lncRNA RNase component of the Mitochondrial RNA Processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well known “telomere disorder”. RMRP binds the telomerase reverse transcriptase protein TERT in some cell lines, raising the possibility that RMRP may play a role in telomere biology.

We sought to determine if a telomere phenotype is present in immune cells from individuals with CHH and explore mechanisms underlying these observations.

We assessed the proliferative capacity and telomere length using flow-FISH (in situ hybridization and flow cytometry) of primary lymphocytes from CHH, carrier relatives and control individuals. The role of telomerase holoenzyme components gene expression and activity were assessed by quantitative PCR and telomere repeat amplification assay (TRAP) from PBMC and enriched lymphocyte cultures.

Lymphocyte cultures from CHH individuals display growth defects in vitro, consistent with an immune deficiency cellular phenotype. Here we show that telomere length and telomerase activity are impaired in primary lymphocyte subsets from cartilage-hair hypoplasia patients. Notably, telomerase activity is affected in a gene dose dependent manner when comparing heterozygote RMRP carriers to individuals with CHH. Telomerase deficiency in CHH is not mediated by abnormal telomerase gene transcript levels relative to endogenous genes.

These findings suggest that telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism.