Clinical, molecular and functional characterization of two novel mutations associated to compound heterozygous FHBL

Risultato della ricerca: Otherpeer review


Introduction. Primary hypobetalipoproteinemia (pHBL) is amonogenic heterogeneous condition characterized by total cholesterol(TC) and/or LDL cholesterol (LDL-C) levels below the 5thpercentile of the reference population.Heterozygous APOB gene mutations are responsible for the majorityof the dominant pHBL causing the familial hypobetalipoproteinemia(FHBL).The clinical phenotype of heterozygous FHBL is usually mild. Thehomozygous or compound heterozygous APOB mutations are insome cases responsible for a more severe biochemical and clinicalphenotype, similar to the abetalipoproteinemia (ABL) due to homozygousmutations in the MTP gene, characterized by intestinalmalabsorption, pigmentary retinal degeneration, ataxic neuropathy,and almost undetectable levels of LDL-C and APOB.methods and Results. In this report we describe the clinical andmolecular characterization of a child with severe hypolipidemiaand a clinical phenotype suggesting the clinical diagnosis of ABL.Parents serum total cholesterol (TC) and LDL cholesterol (LDLC)levels however were below the 5th percentile thus suggestingthat the proband could have been homozygous or compound heterozygousFHBL. Western blot analysis showed the presence oftwo truncated forms of apoB protein of different molecular weightin the serum of the proband; a single truncated form was then observedin the mother on in the father.The direct sequence the apoB gene in the proband allowed to identifytwo novel mutations: a) a mutation of the donor splice site of intron23 of the APOB gene (c.3824+1G>C) and b) a mutation of theacceptor site of intron 23 of of the ApoB gene (c.3825-1G>A). Theparents were heterozygous carriers. Splicing mechanisms of bothmutations were further characterized by minigene assay in vitro.Conclusion. In this report we have characterized at the clinicaland molecular level a rare case of compound heterozygous FHBLwhich carries two novel splicing mutations of the APOB gene affectingthe splicing machinery.
Lingua originaleEnglish
Numero di pagine1
Stato di pubblicazionePublished - 2012


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