Uncommon allele in APO AI . CIII . AIV gene cluster in a family withcongenital generalized Iipodystrophy

Congenital generalized Iipodystrophy is arare inherited disease. One of its featüres is a disturbance in Iipid metabolism characterized by hypercholesterolemia and hypertriglyceridemia. A brother and a sister with congenital generalized lipodystrophy, an 8-year old mal e and a 12-year old female were studied. lhe mother and a 6-year old brother were healthy. lhe genetic analysis of 8stl RFLP of the apo AICIII-AIV gene c1uster showed the presence of the rare 8stl allele (82) in the patients but not in the healthy mother and brother. As this uncommon allele has been reported to be related to high plasma triglyceride leveis, this association could be relevant in explaining in part the hypertriglyceridemia observed in these patients.


C
ongenital generalized lipodystrophy (Seip -Berardinelli syndrome) is arare hereditary disease inherited as an autosomic recessive trait.Its most striking features are extreme paucity of fat in adipose tissue, increased growth rate, muscular/pseudohypertrophy, arid disturbances of carbohydrate and lipid metabolism characterized by insulin resistance and hyperlipidemia.The mechanism behind these alterations is unclear.
The genes coding for apolipoproteins (apo) A-I, C-III, and A-IV are clustered within a 15~Kb DNA segment on the long arm of human chromossome 11.Several DN A polymorphisms have .beenidentified in this gene cluster.Digesting genomic DNA with restriction endonuclease Sstl yields two fragments after hybridization with apoAI probe: 5.7-Kb and4.2-Kb in length (SI allele).In mutated alleles, a 3. the rare allele (S2) could be associated with certain types of hyperlipoproteinemia in which hypertriglyceridemia is a feature l .We describe here the Sstl polymorphism of the apoAI-CIII-AIV gene cluster in a family with congenital generalized lipodystrophy.
A brother and a sister with congenital generalized lipodystrophy, an 8-year old mal e (F.F.) and a 12-year old fémale (A.F.), were studied.The mother and another brother (6-year old, R.F.) were healthy, as shown by clinicaI and laboratory evaluation.The father had died ofunknown causes and it was not possible to know whether he had suffered from any disease.The clinicaI diagnosis of congenital generalized lipodystrophy was made when the children were babies.The -patients (F.F.and A.F.) had a complete absence of adipose tissue.They showed acromegaloid aspect with muscular hypertrophy and phlebomegaly, abdominal protrusion with hepatomegaly, and acanthosis nigricans.Among the laboratory findings, the patients showed normal fasting blood glucose, impaired glucose tolerance and insulin resistance.Other striking features were hypertriglyceridemia and hypercholesterolemia with increased LDL-cholesterol leveIs.kb hypertriglyceridemia, although the mechanism of this association remains an enigma.AaIto-SetiiUi et aI 3 havefound the S2 anele in 16% of healthy controls, 23% of patients with CHD and 62% of unrelated subjects with hypertriglyceridemia.These data are in accord with Rees et al 4 who did not find any normolipemic individual carrying the S2 allele, but reported the presence ofthis anele in 26 out of 74 hypertriglyceridemic subjects.We have found the S2 allele in only 2% of a normolipemic Brazilian population 2 .Other investigators have also indicated that there could be a significant relationship between lipid metabolism disorders and the Sstl polymorphism of the apoAI-CIII-AIV gene complex in patients with hypertriglyceridemia or even hypercholesterolemia.
In the present study the S2 allele was present in the patients with congenital generalized lipodystrophy and absent in the healthy mother and brother.
In conclusion, we have described the presence of the uncommon allele S2 in the apoAI-CIII-AIV gene cluster in a family with congenital generalized lipodystrophy, which could contribute to the high leveIs of plasma triglycerides observed in the patients.Moreover, although one cannot make any inferences about allelic association from only two cases in one family, the present study has provided additional evidence that genetic variation at this site could be involved in hypertriglyceridemia. .7

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DNA was isolated from the nuclear fraction of 5 ml of venous blood, and used for genomic blotting analysis.Restriction fragment length polymorphism (RFLP) studies with restriction endonuclease Sstl were performed as described 2 .
Molecular analysis of Sstl RFLP of the apoAI-CIII-AIV gene complex showed in the mother and young brother the 5.7-and 4.2-Kb long fragments (genotype StSt)' while in the patients, 5.7,4.2 and 3.2-Kb long fragments were yielded (genotype SIS2) (Figure 1).
Several genetic mutations have been linked to alterations in plasma lipoproteins.It has been suggested that variant aneles of the non-coding region of the apoAI~CIII-AIV gene cluster constitute a genetic marker for