Abstract 134: A Double Heterozygote for LCAT and ABCA1 Mutations Accounts for Severe Hypoalphalipoproteinemia

We report a family with extremely depressed high density lipoprotein (HDL) cholesterol (C) levels. The proband, a 27 year-old male of Asian Indian origin, was identified on routine lipid screening to have an HDL-C of 9mg/dL. His 24 year-old brother had an HDL-C of 6mg/dL and was therefore referred to a local lipid clinic in 1997. Both brothers were asymptomatic. The nuclear family was comprised of another brother and a mother living in India; their father had died previously from an undetermined cause. The parents were second cousins. Blood was obtained from members of the extended family and showed that the mother’s HDL-C was reduced at 29mg/dL, while the 3rd bother had a normal HDL-C at 54mg/dL. Based on the above scenario, a homozygous mutation most likely involving ABCA1 was presumed to be responsible for this lipoprotein profile. However, microsatellite marker analyses of the ABCA1 locus showed no homozygosity pattern in the two affected brothers. Further analyses of the APOA1-C3-A4 locus similarly failed to show homozygosity in the affected brothers. Plasma activities of both salt-stimulated paraoxanase and LCAT were at the low end of normal. Direct sequence analyses of the LCAT gene showed all three brothers were heterozygous for the Arg423His mutation, while the mother’s LCAT gene sequence was normal. No further work was pursued until 2011, when this family’s DNA was re-examined by direct sequencing. On this occasion, a heterozygous mutation in ABCA1 was found, namely Arg1270X in the 2 affected brothers and their mother. To our knowledge, this is the first report of ’double heterozygosity’ for LCAT and ABCA1 mutations producing severe hypoalphalipoproteinemia. Further, simple heterozygosity for the ABCA1 Arg1270X mutation had a co-dominant influence, moderately reducing HDL-C levels. In contrast, simple heterozygosity for the LCAT Arg423His mutation had no effect on HDL-C, but in the presence of ABCA1 Arg1270X it contributed to markedly reduced HDL-C. This case report highlights a potential pitfall in human genetic studies, namely assuming a particular inheritance pattern based upon family structure. It also highlights the value of perseverance by searching for causative mutations in more than one gene.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.