Asunto(s)
Árabes , Hiperlipoproteinemia Tipo I/genética , ADN/genética , Análisis Mutacional de ADN , Humanos , Hiperlipoproteinemia Tipo I/enzimología , Hiperlipoproteinemia Tipo I/etnología , Recién Nacido , Israel/epidemiología , Lipoproteína Lipasa/sangre , Lipoproteína Lipasa/genética , Masculino , Mutación , Linaje , Reacción en Cadena de la Polimerasa , Índice de Severidad de la EnfermedadAsunto(s)
Apolipoproteínas A/genética , Pueblo Asiatico/genética , Hiperlipoproteinemia Tipo I/genética , Mutación , Sitios de Empalme de ARN , Apolipoproteína A-V , Apolipoproteínas A/sangre , Análisis Mutacional de ADN , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo I/sangre , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Hiperlipoproteinemia Tipo I/etnología , Intrones , Japón , Masculino , Persona de Mediana EdadRESUMEN
Recently, a (t-->g) transition at nucleotide -93 in the lipoprotein lipase (LPL) gene promoter has been observed in Caucasians. Here, we have compared the frequency of the -93g carriers in three distinct populations (Caucasians, South African Blacks, and Chinese). The carrier frequency in the Caucasian population was 1.7% (4/232), which was in contrast to the South African Black population, which had a frequency for this allele of 76.4% (123/161) of the individuals tested. This transition was not observed in the Chinese population under study. Near complete linkage disequilibrium between the -93g and the previously described D9N mutation was observed in the Caucasian population but not in South African Blacks. To further assess the ancestral origins of these DNA changes, DNA haplotyping using a CA repeat 5' to these substitutions was performed. The -93t allele was associated with only a few specific dinucleotide repeat sizes. In contrast, the -93g allele occurred on chromosomes with many different repeat lengths. The broad distribution of repeats on -93g carrying chromosomes, their high frequency in the South African Black population, and the conservation of the -93g allele among different species may suggest that the -93g allele is the ancestral allele on which a transition to t and the D9N mutations arose. The very high frequency of the -93g allele distinct from the N9 allele in a cohort of Black South Africans allowed us to specifically assess the phenotypic effects of the -93g allele on lipids. Individuals homozygous for the g allele at -93 showed mildly decreased triglycerides compared with individuals homozygous for the t allele (1.14 +/- 0.66 mmol/L versus 0.82 +/- 0.3; P = .04). Thus, the -93g allele in this cohort is associated with low plasma triglyceride levels.
Asunto(s)
Pueblo Asiatico/genética , Población Negra/genética , Etnicidad/genética , Variación Genética , Hiperlipidemia Familiar Combinada/etnología , Hiperlipoproteinemia Tipo I/etnología , Lipoproteína Lipasa/genética , Mutación Puntual , Regiones Promotoras Genéticas/genética , Población Blanca/genética , Adulto , Alelos , China/etnología , Colesterol/sangre , Estudios de Cohortes , Análisis Mutacional de ADN , Repeticiones de Dinucleótido , Frecuencia de los Genes , Heterogeneidad Genética , Ligamiento Genético , Haplotipos/genética , Humanos , Hiperlipidemia Familiar Combinada/epidemiología , Hiperlipidemia Familiar Combinada/genética , Hiperlipoproteinemia Tipo I/epidemiología , Hiperlipoproteinemia Tipo I/genética , Masculino , Massachusetts/epidemiología , Persona de Mediana Edad , Países Bajos/epidemiología , Fenotipo , Sudáfrica/etnología , Triglicéridos/sangreRESUMEN
Mutations in the lipoprotein lipase (LPL) gene are the most common cause of familial chylomicronemia. Here we define the molecular basis of LPL deficiency in four patients of German, French, Dutch, and Chinese descent. We show that two of the probands of Dutch and Chinese origin have a previously described Arg243His mutation while the patients of German and French descent have a novel Arg243Cys substitution in their LPL gene. Haplotype analysis is in favour of two separate origins for the Arg243Cys substitution which together with the Arg243His mutation would implicate three recurrent mutations involving the first and second nucleotides of the codon encoding Arg243 of the LPL gene. The recurrent mutations affecting the first and second nucleotide of CGC coding for the normal Arg residue are support for the high mutability of CpG dinucleotides within the LPL gene.
Asunto(s)
Arginina/genética , Hiperlipoproteinemia Tipo I/genética , Mutación Puntual/genética , Adulto , Secuencia de Aminoácidos , Arginina/análisis , Secuencia de Bases , Línea Celular , Preescolar , China , Europa (Continente) , Exones/genética , Regulación de la Expresión Génica/genética , Haplotipos/genética , Humanos , Hiperlipoproteinemia Tipo I/etnología , Lipoproteína Lipasa/análisis , Lipoproteína Lipasa/genética , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutagénesis , Polimorfismo de Longitud del Fragmento de Restricción , Análisis de Secuencia de ADNAsunto(s)
Pruebas Genéticas/métodos , Hiperlipoproteinemia Tipo I/genética , Lipoproteína Lipasa/genética , Mutación Puntual , Polimorfismo de Longitud del Fragmento de Restricción , Secuencia de Bases , Análisis Mutacional de ADN/métodos , Cartilla de ADN , Enzimas de Restricción del ADN , Francia/etnología , Humanos , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/etnología , Leucina/genética , Lipoproteína Lipasa/deficiencia , Epidemiología Molecular , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Prolina/genética , Quebec/epidemiologíaRESUMEN
Mutations in the human lipoprotein lipase (LPL) gene are one of the major causes of familial chylomicronemia. We have characterized two polymorphic GT microsatellites flanking this gene. Two LPL mutations that are extremely frequent in French Canadians appear to be in complete linkage disequilibrium with specific LPL microsatellite haplotypes indicating a founder effect within this population.
Asunto(s)
ADN Satélite/análisis , Hiperlipoproteinemia Tipo I/etnología , Hiperlipoproteinemia Tipo I/genética , Lipoproteína Lipasa/genética , Mutación , Adulto , Alelos , Secuencia de Bases , Canadá , Distribución de Chi-Cuadrado , Niño , Análisis Mutacional de ADN , Femenino , Francia/etnología , Frecuencia de los Genes , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Datos de Secuencia Molecular , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Quebec , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
Mutations in the lipoprotein lipase (LPL) gene, leading to partial or total inactivation of the enzyme, result in a hereditary clinical syndrome called familial LPL deficiency. The French Canadian population, which is primarily and historically located in the province of Québec, has the highest worldwide frequency of LPL-deficient patients. We have analyzed the prevalence, spatial distribution, and genealogy in the Québec population of a LPL gene mutation, M-207 (P207L in conventional notation), which changes the amino acid proline to leucine in position 207 of the LPL protein and inactivates the enzyme. Our results show that M-207 is the most prevalent LPL gene mutation among French Canadians and accounts for the largest proportion of LPL-deficient patients in this population. Genealogical reconstruction of French Canadian LPL-deficient patients point to 16 founders of M-207, all of whom migrated to Québec in the early seventeenth century from the north-western part of France, especially from the region of Perche. Most of the carriers of M-207 are, at present, found in Charlevoix, Saguenay-Lac-St-Jean regions of eastern Québec. On the basis of the number of homozygote M-207 LPL-deficient patients so far identified, we estimate that there are at least 31,000 carriers of this mutation in the province of Québec. This constitutes a large pool of individuals at risk for atherosclerosis and other lipid-related diseases, since LPL deficiency is considered to be a significant contributing factor in the etiology and development of these diseases.
Asunto(s)
Hiperlipoproteinemia Tipo I/genética , Lipoproteína Lipasa/genética , Mutación/genética , Alelos , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Heterocigoto , Homocigoto , Humanos , Hiperlipoproteinemia Tipo I/etnología , Incidencia , Masculino , Datos de Secuencia Molecular , Linaje , QuebecRESUMEN
Familial lipoprotein lipase deficiency (FLD) is of particular interest to the French Canadian population of Québec since the largest concentration of homozygotes and carriers of this genetic disease in the world resides in this area. We have previously described a missense mutation (M-188) in the lipoprotein lipase (LPL) gene which was present in FLD patients belonging to different ancestries, including a number of French Canadians (Monsalve MV et al. J Clin Invest 1990: 86: 728-734). In the present report, we show that this mutation, although found in largest absolute numbers among French Canadians as compared to other groups in the world, accounts for only a small proportion (24%) of all the LPL mutant alleles in this population. The M-188 occurs either in the homozygote state or as a compound heterozygote with another LPL mutation. Analysis of geographic distribution indicates that the M-188 is more prevalent in western Québec, with the highest carrier rate in the Mauricie region. Genealogical reconstruction leads to the recognition of four founders for M-188, all emigrants from France to Québec in the 17th century.
Asunto(s)
Hiperlipoproteinemia Tipo I/genética , Lipoproteína Lipasa/genética , Mutación/genética , Secuencia de Bases , Femenino , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo I/etnología , Masculino , Datos de Secuencia Molecular , Prevalencia , Quebec/epidemiologíaRESUMEN
Familial hyperchylomicronemia has reached a high prevalence in the French Canadian population of eastern Quebec. The birth places of 58 carriers identified through the birth of one affected child clustered in three regions. The genealogies of these 58 individuals showed that no founder was common to all of them. Three sets of founders were found, one for each region, with little overlapping between two regions. These results strongly suggest that more than one mutation, introduced by the French migrants in the 17th century, are segregating in the French Canadian population. Perche, a region situated between Paris and Normandy, appeared to be the most likely putative center of diffusion of at least one mutation in the lipoprotein lipase gene segregating in the modern-day French Canadian population of Quebec.
Asunto(s)
Hiperlipoproteinemia Tipo I/etnología , Francia/etnología , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo I/epidemiología , Linaje , Prevalencia , Quebec/etnologíaRESUMEN
We examined 56 French Canadians, aged 1 week to 54 years, from eastern Quebec who were referred to the Laval University Lipid Research Centre and in whom coincidental finding (in 46% of the cases), abdominal pain (in 32%) or family screening (in 22%) led to the diagnosis of primary lipoprotein-lipase-activity deficiency (familial hyperchylomicronemia). Half of the patients had one or more of the following signs: lipemia retinalis, eruptive xanthomas, splenomegaly and hepatomegaly; the plasma triglyceride concentrations were significantly higher (greater than 40 mmol/L) among these patients than among those without clinical signs (mean 21.7 [standard deviation 13.5] mmol/L). The prevalence rate of this disorder was 30 times higher than the previously published rate and was highest in the counties of Charlevoix and Saguenay-Lac-St-Jean (200 and 100 cases per million respectively) because of the distinct demographic history of these areas. Because of a founder effect an autosomal recessive gene involved in lipoprotein-lipase expression or activation has probably been disseminated among this isolated French Canadian population.