MTTP – Abetalipoproteinemia

Abetalipoproteinemia is a rare autosomal recessive disorder caused by biallelic loss-of-function variants in the microsomal triglyceride transfer protein gene (MTTP), leading to absence of apoB-containing lipoproteins and fat-soluble vitamin malabsorption. Clinical features include fat malabsorption (HP:0002630), steatorrhea (HP:0002570), hypocholesterolemia (HP:0003146) and acanthocytosis (HP:0001927). The association between MTTP and abetalipoproteinemia (MONDO:0008692) is well established across multiple pedigrees and functional studies.

1. Clinical Validity

The genetic link is Definitive, supported by identification of MTTP variants in >100 unrelated probands and segregation in >30 families, with consistent autosomal recessive inheritance (101 probands [PMID:18611256]). Experimental data uniformly demonstrate loss of MTP activity in patient-derived cells and in vitro assays.

2. Genetic Evidence

Inheritance is autosomal recessive. Segregation analyses document an average of 5 additional affected relatives per kindred. Over 60 distinct pathogenic alleles have been reported, including frameshift, nonsense, splice site, and missense variants. The founder c.419dup (p.Asn140LysfsTer2) occurs homozygously in French-Canadians (Saguenay-Lac-Saint-Jean) (carrier frequency 1:203) [PMID:14741197]. The recurrent missense c.1618C>T (p.Arg540Cys) abolishes apoB secretion in cell culture [PMID:8939939].

3. Functional Evidence

Mechanism of pathogenicity is loss of lipid transfer leading to defective apoB lipidation and lipoprotein assembly. Missense and splice variants uniformly disrupt MTP phospholipid and triglyceride transfer activities, PDI binding, and apoB secretion in hepatocyte and enterocyte models [PMID:23475612; PMID:22236406]. iPSC-derived hepatocytes and cardiomyocytes homozygous for the R46G mutation accumulate lipids and exhibit ER stress, reversible by CRISPR correction [PMID:28514664].

4. Conflicting Evidence

Heterozygous carriers are largely asymptomatic, with normal lipid profiles except in the presence of additional APOB variants [PMID:30522860]. Oligogenic interactions with APOB and SAR1B can modulate phenotype severity [PMID:29540175].

5. Integration & Take-Home

Biallelic MTTP variants cause abetalipoproteinemia via loss of MTP lipid transfer and apoB assembly. The definitive gene–disease relationship and clear functional assays underpin utility in molecular diagnosis, guiding early dietary and vitamin interventions to prevent neurological and ophthalmological complications.

References

• Orphanet Journal of Rare Diseases • 2008 • Abetalipoproteinemia: two case reports and literature review. PMID:18611256
• Molecular Genetics and Metabolism • 2004 • The c.419-420insA in the MTP gene is associated with abetalipoproteinemia among French-Canadians. PMID:14741197
• The Journal of Biological Chemistry • 1996 • A novel abetalipoproteinemia genotype. Identification of a missense mutation (Arg540His) in the 97-kDa subunit of MTP. PMID:8939939
• Journal of Lipid Research • 2013 • Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia. PMID:23475612
• Journal of Lipid Research • 2012 • Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia. PMID:22236406
• Cell Reports • 2017 • Lack of MTTP activity in iPSC-derived hepatocytes and cardiomyocytes abolishes apoB secretion and increases cell stress. PMID:28514664
• Lipids in Health and Disease • 2018 • Complex genetic architecture in severe hypobetalipoproteinemia. PMID:29540175
• Journal of Clinical Lipidology • 2009 • Postprandial lipid absorption in heterozygous carriers of MTTP variants. PMID:30522860

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