Abstract
Pleiotropic, recessively inherited cartilage-hair hypoplasia (CHH) is due to mutations in the untranslated RMRP gene on chromosome 9p13-p12 encoding the RNA component of RNase MRP endoribonuclease. We describe 36 different mutations in this gene in 91 Finnish and 44 non-Finnish CHH families. Based on their nature and localisation, these mutations can be classified into three categories: mutations affecting the promoter region, small changes of conserved nucleotides in the transcript, and insertions and duplications in the 5′ end of the transcript. The only known functional region that seemed to avoid mutations was a nucleolar localisation signal region between nucleotides 23–62. The most common mutation in CHH patients was a base substitution G for A at nucleotide 70. This mutation contributed 92% of the mutations in the Finnish CHH patients. Our results using linkage disequilibrium based maximum likelihood estimates with close markers, genealogical studies, and haplotype data suggested that the mutation was introduced to Finland some 3900–4800 years ago, and before the expansion of the population. The same major mutation accounted for 48% of the mutations among CHH patients from other parts of Europe, North and South America, the Near East, and Australia. In the non-Finnish CHH families, the A70G mutation segregated with the same major haplotype, although shorter, as in most of the Finnish families. In 23 out of these 27 chromosomes, the common region extended over 60 kb, and, therefore, all the chromosomes most likely arose from a solitary event many thousands of years ago.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
McKusick VA, Eldridge R, Hostetler JA, Ruangwit U, Egeland JA . Dwarfism in the Amish. II. Cartilage-hair hypoplasia Bull Johns Hopkins Hosp 1965 116: 231–272
Mäkitie O . Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 Patients J Med Genet 1992 29: 652–655
Mäkitie O, Kaitila I . Cartilage-hair hypoplasia – clinical manifestations in 108 Finnish patients Eur J Pediatr 1993 152: 211–217
Mäkitie O, Pukkala E, Teppo L, Kaitila I . Increased incidence of cancer patients with cartilage-hair hypoplasia J Pediatr 1999 134: 315–318
Mäkitie O, Pukkala E, Kaitila I . Increased mortality in cartilage-hair hypoplasia Arch Dis Child 2001 84: 65–67
Mäkitie OM, Tapanainen OJ, Dunkel L, Siimes MA . Impaired spermatogenesis: an unrecognized feature of cartilage-hair hypoplasia Ann Med 2001 33: 201–205
Sulisalo T, Francomano CA, Sistonen P et al. High-resolution genetic mapping of the cartilage-hair hypoplasia (CHH) gene in Amish and Finnish families Genomics 1994 20: 347–353
Sulisalo T, Sistonen P, Hästbacka J et al. Cartilage-hair hypoplasia gene assigned to chromosome 9 by linkage analysis Nat Genet 1993 3: 338–341
Sulisalo T, Klockars J, Mäkitie O et al. High-resolution linkage-disequilibrium mapping of the cartilage-hair hypoplasia gene Am J Hum Genet 1994 55: 937–945
McKusick VA . Ellis-van Creveld syndrome and the Amish Nat Genet 2000 24: 203–204
Vakkilainen T, Kivipensas P, Kaitila I, de la Chapelle A, Ridanpää M . Integrated high-resolution BAC, P1, and transcript map of the CHH region in chromosome 9p13 Genomics 1999 59: 319–325
Ridanpää M, van Eenennaam H, Pelin K et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia Cell 2001 104: 195–203
van Eenennaam H, Jarrous N, van Venrooij WJ, Pruijn GJ . Architecture and function of the human endonucleases RNase P and RNase MRP IUBMB Life 2000 49: 265–272
Norio R, Nevanlinna HR, Perheentupa J . Hereditary diseases in Finland; rare flora in rare soil Ann Clin Res 1973 5: 109–141
Nevanlinna HR . The Finnish population structure. A genetic and genealogical study Hereditas 1972 71: 195–236
de la Chapelle A . Disease gene mapping in isolated human populations: the example of Finland J Med Genet 1993 30: 857–865
de la Chapelle A, Wright F . Linkage disequilibrium mapping in isolated populations: The example of Finland revisited Proc Natl Acad Sci 1998 95: 12416–12423
Lahiri DK, Bye S, Nürnberger Jr JI, Hodes ME, Crisp M . A non-organic and non-enzymatic extraction method gives higher yields of genomic DNA from whole-blood samples than do nine other methods tested J Biochem Biophys Methods 1992 25: 193–205
Pelin K, Hilpelä P, Donner K et al. Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy Proc Natl Acad Sci USA 1999 96: 2305–2310
Sulisalo T, Mäkitie O, Sistonen P et al. Uniparental disomy in cartilage-hair hypoplasia Eur J Hum Genet 1997 5: 35–42
Rannala B, Slatkin M . Likelihood analysis of disequilibrium mapping, and related problems Am J Hum Genet 1998 62: 459–473
Risch N, Teng J . The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases I. DNA pooling Genome Res 1998 8: 1273–1288
Labuda M, Labuda D, Korab-Laskowska M et al. Linkage disequilibrium analysis in young populations: pseudo-vitamin D-deficiency rickets and the founder effect in French Canadians Am J Hum Genet 1996 59: 633–643
Schmitt ME, Bennett JL, Dairaghi DJ, Clayton DA . Secondary structure of RNase MRP RNA as predicted by phylogenetic comparison FASEB J 1993 7: 208–213
Sbisà E, Pesole G, Tullo A, Saccone C . The evolution of the RNase P- and RNase MRP-associated RNAs: phylogenetic analysis and nucleotide substitution rate J Mol Evol 1996 43: 46–57
Tremblay M, Vézina H . New estimates of intergenerational time intervals for the calculation of age and origins of mutations Am J Hum Genet 2000 66: 651–658
Jacobsen MR, Cao L-G, Wang Y-L, Pedersen T . Dynamic localization of RNase MRP RNA in the nucleolus observed by fluorescent RNA cytochemistry in living cells J Cell Biol 1995 131: 1649–1658
Schmitt ME, Clayton DA . Yeast site-specific ribonucleoprotein endoribonuclease MRP contains an RNA component homologous to mammalian RNase MRP RNA and essential for cell viability Genes Dev 1992 6: 1975–1985
Li K, Smagula CS, Parsons WJ et al. Subcellular partitioning of MRP RNA assessed by ultrastructural and biochemical analysis J Cell Biol 1994 124: 871–882
Ikonen E, Aula P, Grön K et al. Spectrum of mutations in aspartylglucosaminuria Proc Nat Acad Sci USA 1991 88: 11222–11226
Vesa J, Hellsten E, Verkruyse LA et al. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis Nature 1995 376: 584–587
Järvelä I, Mitchison HM, Munroe PB, O'Rawe AM, Mole SE, Syvänen AC . Rapid diagnostic test for the major mutation underlying Batten disease J Med Genet 1996 33: 1041–1042
Kestilä M, Lenkkeri U, Männikkö M et al. Positionally cloned gene for a novel glomerular protein nephrin is mutated in congenital nephrotic syndrome Mol Cell 1998 1: 575–582
Virtaneva K, D'Amato E, Miao J et al. Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1 Nat Genet 1997 15: 393–396
Acknowledgements
We acknowledge the following clinicians and genetic counselors for sending clinical data and patient samples for this study: L Adès, Australia, J Bonaventure, France, Z Borozowitz, Israel, J Boudames, USA, J Campbell, USA, A Castriota-Scanderbeg, Italy, D Chitayat, Canada, DH Cohn, USA, M Conley, USA, T Costa, Canada, A de Oliveira, USA, CR Dolan, UK, F Elmslie, UK, P Freisinger, Germany, L Jobim, Brazil, M Johnson, USA, H. Kayserili, Turkey, S Langlois, Canada, J Mattheson, USA, W Newman, USA, I Pellier, France, R Saviriayan, Australia, C Scott, USA, T Simon, Germany, S Smithson, UK, M Splitt, UK, E Steichen, Austria, A Superti-Furga, Switzerland, I van der Burgt, The Netherlands, L van Maldergem, Belgium, W Wilcox, USA, L Wilson, UK, R Winter, UK, B Zabel, Germany, P Zack, UK. Professor Albert de la Chapelle is thanked for useful discussions and critical reading of the manuscript. Ahmed Mohamed, Hanna Mäkelä, Katarina Pelin and Riika Salmela are acknowledged for laboratory assistance and collaborative help and Sinikka Lindh for help in the genealogical study and drawing Figures 2B and C. This work was financially supported by The March of Dimes Birth Defects Foundation (6-FY99-586 and 6-FY00-294), the Academy of Finland (grant 38826), Helsinki University's Research Funds, the Helsinki University Central Hospital Fund, the Ulla Hjelt Fund, Finland, and an NIH Program Project grant (2 PO1 HD22657).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ridanpää, M., Sistonen, P., Rockas, S. et al. Worldwide mutation spectrum in cartilage-hair hypoplasia: ancient founder origin of the major70A→G mutation of the untranslated RMRP. Eur J Hum Genet 10, 439–447 (2002). https://doi.org/10.1038/sj.ejhg.5200824
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.ejhg.5200824
Keywords
This article is cited by
-
Oral findings in patients with cartilage-hair hypoplasia - cross-sectional observational study
Orphanet Journal of Rare Diseases (2023)
-
Outcomes of 42 pregnancies in 14 women with cartilage-hair hypoplasia: a retrospective cohort study
Orphanet Journal of Rare Diseases (2020)
-
The human long non-coding RNA gene RMRP has pleiotropic effects and regulates cell-cycle progression at G2
Scientific Reports (2019)
-
Gynecologic assessment of 19 adult females with cartilage-hair hypoplasia – high rate of HPV positivity
Orphanet Journal of Rare Diseases (2018)
-
Cartilage Hair Hypoplasia: Two Unrelated Cases with g.70 A > G Mutation in RMRP Gene
The Indian Journal of Pediatrics (2016)
