Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia

Abetalipoproteinemia (ABL) is an inherited disease characterized by the virtual absence of apolipoprotein B (apoB)-containing lipoproteins from plasma. Only limited numbers of families have been screened for mutations in the microsomal triglyceride transfer protein (MTP) gene. To clarify the genetic...

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Bibliographic Details
Published in:Journal of lipid research 2000-08, Vol.41 (8), p.1199-1204
Main Authors: Ohashi, K, Ishibashi, S, Osuga, J, Tozawa, R, Harada, K, Yahagi, N, Shionoiri, F, Iizuka, Y, Tamura, Y, Nagai, R, Illingworth, D R, Gotoda, T, Yamada, N
Format: Article
Language:English
Subjects:
abetalipoproteinemia
Abetalipoproteinemia - genetics
Adenine
Adolescent
Adult
Animals
apolipoprotein B
Base Sequence
Carrier Proteins - genetics
Carrier Proteins - physiology
cholesterol
COS Cells
DNA, Complementary - chemistry
Female
Frameshift Mutation
Gene Expression
Heterozygote
Humans
Infant
lipoproteins
Male
microsomal triglyceride transfer protein
Mutation
Mutation, Missense
Polymerase Chain Reaction
RNA Splicing
Sequence Analysis, DNA
Transfection
triglycerides
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Summary:Abetalipoproteinemia (ABL) is an inherited disease characterized by the virtual absence of apolipoprotein B (apoB)-containing lipoproteins from plasma. Only limited numbers of families have been screened for mutations in the microsomal triglyceride transfer protein (MTP) gene. To clarify the genetic basis of clinical diversity of ABL, mutations of the MTP gene have been screened in 4 unrelated patients with ABL. Three novel mutations have been identified: a frameshift mutation caused by a single adenine deletion at position 1389 of the cDNA, and a missense mutation, Asn780Tyr, each in homozygous forms; and a splice site mutation, 2218-2A-->G, in a compound heterozygous form. The frameshift and splice site mutations are predicted to encode truncated forms of MTP. When transiently expressed in Cos-1 cells, the Asn780Tyr mutant MTP bound protein disulfide isomerase (PDI) but displayed negligible MTP activity. It is of interest that the patient having the Asn780Tyr mutation, a 27-year-old male, has none of the manifestations characteristic of classic ABL even though his plasma apoB and vitamin E were virtually undetectable. These results indicated that defects of the MTP gene are the proximal cause of ABL.
ISSN:0022-2275
DOI:10.1016/s0022-2275(20)33426-x