β-glucocerebrosidase gene locus as a link for Gaucher's disease and familial hypo-α-lipoproteinaemia

被引:36
作者
Pocovi, M
Cenarro, A
Civeira, F
Torralba, MA
Perez-Calvo, JI
Mozas, P
Giraldo, P
Giralt, M
Myers, RH
Cupples, LA
Ordovas, JM
机构
[1] Univ Zaragoza, Fac Sci, Dept Biochem Mol & Cellular Biol, E-50009 Zaragoza, Spain
[2] Univ Hosp, Dept Internal Med, Zaragoza, Spain
[3] Hosp Miguel Servet, Dept Internal Med, Zaragoza, Spain
[4] Hosp Miguel Servet, Dept Haematol, Zaragoza, Spain
[5] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA
[6] Boston Univ, Sch Med, Dept Publ Hlth, Boston, MA 02118 USA
[7] Tufts Univ, Lipid Metab Lab JM HNRCA, Boston, MA 02111 USA
关键词
D O I
10.1016/S0140-6736(97)09490-7
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background Gaucher's disease is the most common lysosomal storage disorder, caused by deficiency of glucocerebrosidase resulting from homozygosity for any of several mutations of the glucocerebrosidase gene locus. Affected people have decreased concentrations of LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C). We assessed the association between mutations in the glucocerebrosidase locus and hypo-alpha-lipoproteinaemia. Methods We studied 258 people from 43 unrelated Spanish families. 57 participants were affected, 137 were nonaffected carriers, and 64 were non-carriers. We determined glucocerebrosidase genotypes and measured plasmid lipids, apolipoproteins A-I, B, and E, and leucocyte glucocerebrosidase activity. Findings The most common glucocerebrosidase mutations were N37OS (45%), L444P (23%), and G377S (5%). Deletions and recombinants accounted for another 5%, and point mutations in exons 5, 6, 9, and 10 were present in 12%, Affected participants had lower LDL-C and HDL-C concentrations than non-affected carriers (p<0.001) and non-carriers (p<0 001). HDL-C values were also significantly different between the non-affected carriers and non-carriers. Mutations at this locus may account for as much as 19.5% of the genetic variability in HDL-C in the population studied. Interpretation Heterozygosity for these mutations at the glucocerebrosidase locus does not result in clinical expression of Gaucher's disease but can decrease HDLC concentrations, Given the high frequency of these mutations, the glucocerebrosidase locus might lead to familial low alpha-lipoproteinaemia in up to 2% of the general population and be one of the most common known genetic causes of HDL-C.
引用
收藏
页码:1919 / 1923
页数:5
相关论文
共 27 条
[1]   Identification of scavenger receptor SR-BI as a high density lipoprotein receptor [J].
Acton, S ;
Rigotti, A ;
Landschulz, KT ;
Xu, SZ ;
Hobbs, HH ;
Krieger, M .
SCIENCE, 1996, 271 (5248) :518-520
[2]   TYPE-1 GAUCHER DISEASE - MOLECULAR, BIOCHEMICAL, AND CLINICAL CHARACTERIZATION OF PATIENTS FROM NORTHERN PORTUGAL [J].
AMARAL, O ;
LACERDA, L ;
SANTOS, R ;
PINTO, RA ;
AERTS, H ;
MIRANDA, MCS .
BIOCHEMICAL MEDICINE AND METABOLIC BIOLOGY, 1993, 49 (01) :97-107
[3]   THE FACILE DETECTION OF THE NT 1226 MUTATION OF GLUCOCEREBROSIDASE BY MISMATCHED PCR [J].
BEUTLER, E ;
GELBART, T ;
WEST, C .
CLINICA CHIMICA ACTA, 1990, 194 (2-3) :161-166
[4]   ERRONEOUS ASSIGNMENT OF GAUCHER DISEASE GENOTYPE AS A CONSEQUENCE OF A COMPLETE GENE DELETION [J].
BEUTLER, E ;
GELBART, T .
HUMAN MUTATION, 1994, 4 (03) :212-216
[5]  
BEUTLER E, 1991, NEW ENGL J MED, V325, P1354
[6]   GLUCOCEREBROSIDASE MUTATIONS IN GAUCHER DISEASE [J].
BEUTLER, E ;
DEMINA, A ;
GELBART, T .
MOLECULAR MEDICINE, 1994, 1 (01) :82-92
[7]  
BEUTLER E, 1993, AM J HUM GENET, V52, P85
[8]  
Beutler E., 1995, METABOLIC MOL BASES, P2641
[9]   THE USE OF MEASURED GENOTYPE INFORMATION IN THE ANALYSIS OF QUANTITATIVE PHENOTYPES IN MAN .3. SIMULTANEOUS ESTIMATION OF THE FREQUENCIES AND EFFECTS OF THE APOLIPOPROTEIN E POLYMORPHISM AND RESIDUAL POLYGENETIC EFFECTS ON CHOLESTEROL, BETA-LIPOPROTEIN AND TRIGLYCERIDE LEVELS [J].
BOERWINKLE, E ;
SING, CF .
ANNALS OF HUMAN GENETICS, 1987, 51 :211-226
[10]   Genetic fine localization of the beta-glucocerebrosidase (GBA) and prosaposin (PSAP) genes: Implications for Gaucher disease [J].
Cormand, B ;
Montfort, M ;
Chabas, A ;
Vilageliu, L ;
Grinberg, D .
HUMAN GENETICS, 1997, 100 (01) :75-79