ClinVar Genomic variation as it relates to human health

In a patient with lipoprotein lipase deficiency (238600) reported by Wilson et al. (1983), Emi et al. (1990) demonstrated homozygosity a G-to-A transition at nucleotide 818 in exon 5 of the LPL gene, resulting in a gly188-to-glu (G188E) substitution in the mature protein. The substitution was demonstrated by a study of LPL cDNA prepared from the adipose tissue of the patient. Hybridization of genomic DNA with allele-specific oligonucleotides confirmed the patient's homozygosity and showed the carrier status for this mutation among relatives of the patient in whom the mutation was associated with hypertriglyceridemia. Monsalve et al. (1990) found the same mutation in 21 of 88 LPL alleles assessed. The 21 alleles came from 13 unrelated probands with LPL deficiency of French Canadian, English, Polish, German, Dutch, and East Indian ancestry. The mutation altered an AvaII restriction site and allowed a rapid screening test. The mutation occurred on the same haplotype in all the unrelated affected persons, suggesting a common origin. The amino acid substitution lies within the longest segment of homology for LPL in different species and results in a protein that is catalytically defective. Haplotype analysis suggested that at least 2 other mutations underlie the high frequency of LPL deficiency in French Canadians in Quebec (Gagne et al., 1989), where the carrier frequency is as high as 1 in 40 in some areas. The presence of the same haplotype background in the non-European cases from the vicinity of Bombay where no European admixture could be identified is surprising. Homozygosity for the G188E mutation results in class I LPL deficiency, i.e., there is absence of enzyme protein. By hybridization of DNA from multiple family members with allele-specific probes for the G188E mutation, Wilson et al. (1990) detected 29 relatives of a homozygous proband who were carriers of the mutant allele. They found that these individuals were prone to a form of familial hypertriglyceridemia that was age modulated, with conspicuous difference between carriers and noncarriers observed only after age 40. Obesity, hyperinsulinemia, and lipid-raising drug use were aggravating factors. Paulweber et al. (1991) found the same mutation in 2 Austrian families with type I hyperlipoproteinemia. Henderson et al. (1992) assessed 16 South African LPL-deficient patients from 9 separate kindreds with the G188E mutation. Nine of the 16 were homozygous for the mutation and were from 4 families, all of Indian descent. Their ancestors originated from villages close to Bombay, India, which suggested a common ancestral mutation, particularly because the mutant allele in each family carried the identical RFLP haplotype. Gilbert et al. (2001) identified homozygosity for the G188E mutation in a 2-year-old patient presenting classic features of familial LPL deficiency including undetectable LPL activity. They found reports of 221 mutations involved in this disorder. The G188E mutation was found in 23.5% of cases. (less)