title: Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia.
abstract: 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." RMRP binds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility that RMRP might 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-fluorescence in situ hybridization (in situ hybridization 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 defects in 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 heterozygote RMRP carriers 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.
  
  
  CONCLUSIONS
  These findings suggest that telomere deficiency is implicated in the CHH disease phenotype through an as yet unidentified mechanism.
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Aubert
authors.affiliation: Clinic for Special Children, Strasburg, Pa.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Strauss
authors.affiliation: Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada; Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; European Research Institute on the Biology of Aging, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands. Electronic address: plansdor@bccrc.ca.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lansdorp
authors.affiliation: Section of Immunology, Allergy and Rheumatology, Texas Children's Hospital, Baylor College of Medicine, Houston, Tex. Electronic address: nlrider@bcm.edu.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Rider
mesh_terms: D000293:Adolescent; D000328:Adult; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D019871:Dyskeratosis Congenita / Q000235:genetics; D005260:Female; D006197:Hair / Q000002:abnormalities* / Q000276:immunology; D006627:Hirschsprung Disease / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology*; D007223:Infant; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000151:congenital* / Q000235:genetics / Q000276:immunology; D010375:Pedigree; D000081207:Primary Immunodeficiency Diseases; D062085:RNA, Long Noncoding / Q000235:genetics*; D016615:Telomere / Q000235:genetics*; D059505:Telomere Homeostasis; D055815:Young Adult
chemical_list: C544035:RMRP non-coding RNA, human; D062085:RNA, Long Noncoding
keywords: Primary immune deficiency; cartilage-hair hypoplasia; lymphocyte; mitochondrial RNA processing endoribonuclease; telomere length