Worldwide mutation spectrum in cartilage-hair hypoplasia:: ancient founder origin of the major 70A→G mutation of the untranslated RMRP

被引:72
作者
Ridanpää, M
Sistonen, P
Rockas, S
Rimoin, DL
Mäkitie, O
Kaitila, I [1 ]
机构
[1] Univ Helsinki, Cent Hosp, Dept Clin Genet, FI-00029 Hus, Finland
[2] Univ Helsinki, Cent Hosp, Hosp Children & Adolescents, FI-00029 Hus, Finland
[3] Univ Helsinki, Biomedicum Helsinki, Folkhalsan Inst Genet, FI-00014 Helsinki, Finland
[4] Univ Helsinki, Biomedicum Helsinki, Dept Med Genet, FI-00014 Helsinki, Finland
[5] Finnish Red Cross Blood Transfus Serv, FI-00310 Helsinki, Finland
[6] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA
关键词
RMRP; mutation; ancestral haplotype; age estimation; untranslated gene; cartilage-hair hypoplasia;
D O I
10.1038/sj.ejhg.5200824
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:439 / 447
页数:9
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