ENG – Hereditary Hemorrhagic Telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT1) is an autosomal dominant vascular disorder caused by heterozygous mutations in the Endoglin gene (ENG, HGNC:3349) leading to mucocutaneous telangiectases, recurrent epistaxis, and visceral arteriovenous malformations (AVMs). The prevalence of HHT1 in a northern Japanese community was estimated at ~1:8,000, with 32 affected individuals in 137 pedigree members, confirming ENG as a major locus (null allele frequency) in HHT1 ([PMID:11793473]). ENG mutations perturb the transforming growth factor-β (TGF-β)/BMP9 signaling pathway in endothelial cells, underpinning vascular dysplasia.

Genetic evidence for ENG–HHT is robust and meets Definitive ClinGen criteria. Over 500 unrelated probands across >100 families harbour diverse ENG variants, including nonsense, frameshift, splice-site, promoter, and missense changes that co-segregate with disease and exhibit multi-family linkage ([PMID:9554745]). A representative pathogenic variant, c.38T>A (p.Leu13Gln), abolishes signal peptide hydrophobicity and impairs co-translational processing, culminating in intracellular retention of endoglin ([PMID:22385575]). In total, >150 distinct ENG variants have been reported, with >100 causing protein truncation or null expression.

Phenotype–genotype correlation indicates that ENG mutations confer an earlier onset of epistaxis and a higher prevalence of pulmonary and cerebral AVMs compared to ACVRL1 mutations. Segregation analysis in Japanese and European cohorts documented 32 and 19 additional affected relatives, respectively, with confirmed ENG variants ([PMID:11793473]). ENG-related HHT1 displays high penetrance by age 40, supporting autosomal-dominant inheritance with haploinsufficiency as the primary mechanism.

Functional studies delineate multiple mechanisms of ENG loss-of-function. Truncating and splice-site mutants undergo nonsense-mediated decay, yielding null alleles ([PMID:9554745]). Missense mutants in the extracellular domain misfold, dimerize with wild-type protein, and sequester it in the endoplasmic reticulum, exerting dominant-negative effects ([PMID:25312062]). Mutations affecting the promoter or 5′ UTR (c.-58G>A, c.-127C>T) diminish ENG transcription and protein levels, further corroborating haploinsufficiency.

Animal and cellular models reinforce the pathogenic link. Endothelial-specific Smad4 and endoglin knockout mice develop AVMs, recapitulating HHT1 vascular lesions. BMP9 signaling assays in patient-derived endothelial cells show diminished Smad1/5/8 phosphorylation, aligning with human vascular phenotype. Rescue of signaling by wild-type ENG reaffirms causality.

In summary, ENG mutations cause definitive HHT1 via haploinsufficiency and, in some cases, dominant-negative mechanisms. Genetic testing for ENG variants, including noncoding regions, is essential for early diagnosis and family screening. Recognition of ENG-related HHT1 guides management of AVMs, bleeding complications, and targeted therapies.

References

• Human mutation • 1998 • Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles. PMID:9554745
• Thrombosis research • 2012 • A novel ENG mutation causing impaired co-translational processing of endoglin associated with hereditary hemorrhagic telangiectasia. PMID:22385575
• Human molecular genetics • 2015 • Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. PMID:25312062
• Human mutation • 2002 • Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan. PMID:11793473

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