Anderson's disease: exclusion of apolipoprotein and intracellular lipid transport genes.
Anderson's disease is a rare, hereditary hypocholesterolemic syndrome characterized by chronic diarrhea, steatorrhea, and failure to thrive associated with the absence of apo B48-containing lipoproteins. To further define the molecular basis of the disease, we studied 8 affected subjects in 7 unrelated families of North African origin after treatment with a low-fat diet. Lipid loading of intestinal biopsies persisted, but the pattern and extent of loading was variable among the patients. Electron microscopy showed lipoprotein-like particles in membrane-bound compartments, the densities (0.65 to 7.5 particles/mu(2)) and the mean diameters (169 to 580 nm) of which were, in general, significantly larger than in a normal fed subject (0.66 particles/mu(2), 209 nm mean diameter). There were also large lipid particles having diameters up to 7043 nm (average diameters from 368 to 2127 nm) that were not surrounded by a membrane. Rarely, lipoprotein-like particles 50 to 150 nm in diameter were observed in the intercellular spaces. Intestinal organ culture showed that apo B and apo AIV were synthesized with apparently normal molecular weights and that small amounts were secreted in lipid-bound forms (density <1.006 g/mL). Normal microsomal triglyceride transfer protein (MTP) and activity were also detected in intestinal biopsies. Segregation analyses of 4 families excluded, as a cause of the disease, significant regions of the genome surrounding the genes for apo AI, AIV, B, CI, CII, CIII, and E, as were the genes encoding 3 proteins involved in intracellular lipid transport, MTP, and fatty acid binding proteins 1 and 2. The results suggest that a factor other than apoproteins and MTP are important for human intestinal chylomicron assembly and secretion.
Dannoura
A H
AH
Centre de Génétique Moléculaire, Centre National de la Recherche Scientifique, Associé à l'Université Pierre et Marie Curie, Paris, France.
Berriot-Varoqueaux
N
N
Amati
P
P
Abadie
V
V
Verthier
N
N
Schmitz
J
J
Wetterau
J R
JR
Samson-Bouma
M E
ME
Aggerbeck
L P
LP
D000328:Adult; D017668:Age of Onset; D001054:Apolipoproteins A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D001056:Apolipoproteins C / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D001706:Biopsy; D002894:Chromosomes, Human, Pair 4; D002914:Chylomicrons / Q000378:metabolism; D004276:DNA, Satellite / Q000032:analysis; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D007408:Intestinal Absorption / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008286:Malabsorption Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D009924:Organ Culture Techniques; D010375:Pedigree; D011110:Polymorphism, Genetic; D014280:Triglycerides / Q000096:biosynthesis / Q000378:metabolism*
D001054:Apolipoproteins A; D001055:Apolipoproteins B; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D002914:Chylomicrons; D004276:DNA, Satellite; D014280:Triglycerides