Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia

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Background:Mutations in the long noncoding RNA 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.”RMRPbinds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility thatRMRPmight play a role in telomere biology.Objective:We sought to determine whether a telomere phenotype is present in immune cells from patients with CHH and explore mechanisms underlying these observations.Methods:We assessed proliferative capacity and telomere length using flow–fluorescencein situhybridization (in situhybridization and flow cytometry) of primary lymphocytes from patients with CHH, carrier relatives, and control subjects. The role of telomerase holoenzyme components in gene expression and activity were assessed by using quantitative PCR and the telomere repeat amplification protocol from PBMCs and enriched lymphocyte cultures.Results:Lymphocyte cultures from patients with CHH display growth defectsin vitro, which is consistent with an immune deficiency cellular phenotype. Here we show that telomere length and telomerase activity are impaired in primary lymphocyte subsets from patients with CHH. Notably, telomerase activity is affected in a gene dose-dependent manner when comparing heterozygoteRMRPcarriers with patients with CHH. Telomerase deficiency in patients with CHH is not mediated by abnormal telomerase gene transcript levels relative to those of endogenous genes.Conclusion:These findings suggest that telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism.Graphical abstract

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