Abetalipoproteinemia Caused by Maternal Isodisomy of Chromosome 4q Containing an Intron 9 Splice Acceptor Mutation in the Microsomal Triglyceride Transfer Protein Gene

Abstract

Abstract-Uniparental disomy (UPD), a rare inheritance of 2 copies of a single chromosome homolog or a region of a chromosome from one parent, can result in various autosomal recessive diseases. Abetalipoproteinemia (ABL) is a rare autosomal recessive deficiency of apoB-containing lipoproteins caused by a microsomal triglyceride transfer protein (MTP) deficiency. In this study, we describe a patient with ABL inherited as a homozygous intron 9 splice acceptor G(Ϫ1)-to-A mutation of the transfer protein gene. This mutation alters the splicing of the mRNA, resulting in a 36 amino acids, in-frame deletion of sequence encoded by exon 10. We analyzed chromosome 4, including MTP gene (4q22-24), using short tandem repeat markers. The proband has only his mother's genes in chromosome 4q spanning a 150-centimorgan region; ie, segmental maternal isodisomy 4q21-35, probably due to mitotic recombination. Nonpaternity between the proband and his father was excluded using 6 polymorphic markers from different chromosomes (paternity probability, 0.999). Maternal isodisomy (maternal UPD 4q) was the basis for homozygosity of the MTP gene mutation in this patient. (Arterioscler Thromb Vasc Biol. 1999;19

Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia

“…The majority of the mutations reported following sequence analysis of the MTP gene or cDNA in ABL subjects are frameshift, nonsense, and splice site mutations that are predicted to encode truncated forms of MTP completely devoid of function (20)(21)(22)(23)(24)(25)(26)(27)(28). However, a few missense mutations, R540H ( 23,25 ), S590I ( 25,29 ), N780Y ( 7,26 ), D384A ( 23,30 ), and G746E ( 25 ) have been described.…”

Congenital afibrinogenaemia caused by uniparental isodisomy of chromosome 4 containing a novel 15-kb deletion involving fibrinogen Aα-chain gene

“…Only five cases of maternal UPD for chromosome 4 have been reported so far. Three were partial UPDs, involving 4q21 -35 in a Japanese man affected by abetalipoproteinaemia, 15 4p13 -16 in a patient affected by Ellis-van Creveld syndrome, 16 and 4p15 -16 in a child with trisomy 21; 17 one was a complete UPD in a normally developed foetus who died in the uterus probably because of the high level of mosaicism for trisomy 4 found in placental trophoblast, 18 and one was a case of isochromosome 4 (46, À4, À4, þ i4q, þ i4p) in a woman with multiple miscarriages. 19 This study describes the first case of congenital afibrinogenaemia caused by uniparental isodisomy (iUPD) of chromosome 4 containing a novel homozygous large deletion (approximately 15 kb).…”

Extreme Contrast of Postprandial Remnant-Like Particles Formed in Abetalipoproteinemia and Homozygous Familial Hypobetalipoproteinemia

“…He was born from a non-consanguineous marriage and was diagnosed with ABL caused by maternal uniparental disomy of intron 9 splice donor site mutation (c.1237-1 G >A , p . Q 4 1 3 _ K 4 4 8 d e l ) o f th e M T T P g e n e (RefSeqNM_000253.1), which was previously reported (Yang et al 1999). His serum lipid and apolipoprotein levels, fat-soluble vitamin levels, and other biochemical parameters under vitamin E supplementation therapy are shown in Table 1.…”

“…Serum lipoprotein and RLP-cholesterol distributions were measured using an HPLC system using 0.05-M Trisbuffered acetate (pH 8.0) at a flow rate of 0.7 mL/min (Tosho, Tokyo, Japan) as described elsewhere (Usui et al 2002). Serum levels of vitamin A were measured by HPLC, and those of vitamin E were determined by a fluorimetric method and by RIA (Yang et al 1999), respectively.…”

“…ABL is an extremely rare recessive disorder characterized by undetectable or very low levels of LDL-cholesterol and apoB, failure to thrive, oral fat intolerance, diarrhea, steatorrhea, and acanthocytosis as well as fatty liver and lipid accumulation in enterocytes (Burnett et al 2014a;Hooper and Burnett 2014;Lee and Hegele 2014;Welty 2014;Yang et al 1999). Neurological abnormalities such as spinocerebellar ataxia and retinitis pigmentosa are caused by deficiencies in fat-soluble vitamins.…”