SLC2A10 – Arterial Tortuosity Syndrome

Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disorder characterized by elongation, tortuosity, stenoses, and aneurysm formation in large- and medium-sized arteries. It is caused by biallelic pathogenic variants in the SLC2A10 gene, encoding the facilitative glucose transporter GLUT10. Over 60 probands from more than 25 unrelated families have been reported with ATS (PMID:17935213, PMID:25373504, PMID:16550171, PMID:18774132, PMID:19781076, PMID:28726533, PMID:37619836, PMID:39857743).

Genetic evidence supports autosomal recessive inheritance with homozygous or compound heterozygous variants segregating in consanguineous and non-consanguineous pedigrees. Segregation of biallelic SLC2A10 variants has been observed in at least 19 additional affected relatives across multiple families (PMID:17935213).

The variant spectrum includes nonsense, frameshift, splice-site, and missense mutations distributed throughout the 5-exon gene. Truncating alleles such as c.685C>T (p.Arg229Ter) and c.756C>A (p.Cys252Ter) recur in diverse populations, while founder missense alleles (e.g., c.243C>G, p.Ser81Arg; c.241A>C, p.Ser81Arg) have been described in Middle Eastern and European cohorts.

Functional studies demonstrate that GLUT10 deficiency leads to upregulation of TGFβ signaling in the arterial wall, elastin fiber disorganization, and extracellular matrix defects consistent with human vascular pathology (PMID:16550171, PMID:35302653). Immunofluorescence analyses of patient fibroblasts show impaired GLUT10 membrane localization.

Animal and cellular models further corroborate pathogenicity: zebrafish slc2a10 knock-down reveals developmental expression in vasculature (PMID:21553381), and Gulo;Slc2a10 double-knockout mice exhibit extracellular matrix disarray and mitochondrial respiration defects akin to ATS features (PMID:32307537).

However, mouse models homozygous for certain missense substitutions (Gly128Glu, Ser150Phe) failed to phenocopy vascular anomalies, suggesting allele-specific functional effects or species-specific compensatory mechanisms (PMID:18693279).

In summary, high-penetrance biallelic SLC2A10 variants cause ATS through loss of GLUT10 function and dysregulated TGFβ-mediated vascular remodeling. Definitive classification is supported by extensive genetic and experimental concordance. Key take-home: genetic testing of SLC2A10 informs diagnosis and management of ATS, guiding surveillance and potential TGFβ-targeted therapies.

References

• Nature Genetics • 2006 • Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome PMID:16550171
• Human Mutation • 2008 • Arterial tortuosity syndrome: clinical and molecular findings in 12 newly identified families PMID:17935213
• BMC Medical Genetics • 2014 • Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review PMID:25373504
• American Journal of Medical Genetics Part A • 2012 • Adult presentation of arterial tortuosity syndrome in a 51-year-old woman with a novel homozygous c.1411+1G>A mutation in the SLC2A10 gene PMID:22488877
• Journal of Cutaneous Pathology • 2022 • Ultrastructure abnormalities of collagen and elastin in Arab patients with arterial tortuosity syndrome PMID:35302653
• Human Molecular Genetics • 2020 • Slc2a10 knock-out mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects PMID:32307537
• Genesis • 2008 • Absence of arterial phenotype in mice with homozygous slc2A10 missense substitutions PMID:18693279
• Cornea • 2023 • Ophthalmic Manifestations of Arterial Tortuosity Syndrome: Case Series of Patient and Carriers PMID:36728218

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