The ANTXR2 (Anthrax Toxin Receptor 2) gene encodes a transmembrane protein that is widely expressed across various organs, except for the brain. This protein contains a von Willebrand factor A (vWA) domain that interacts with extracellular matrix proteins, such as collagen VI and laminin, facilitating their transport to lysosomes for degradation.
In addition to its role in extracellular matrix homeostasis, ANTXR2 may also participate in intracellular signaling pathways, potentially triggering phosphorylation or ubiquitination upon substrate binding. This regulatory function influences cellular processes, including protein turnover and degradation.
Mutations in ANTXR2 disrupt these critical functions, leading to collagen VI accumulation in the extracellular matrix. This accumulation contributes to the progressive tissue fibrosis and joint contractures seen in HFS.
Classification of ANTXR2 variants (Deuquet J., 2012):
• Class I: Missense variants in the vWA domain, affecting extracellular matrix interactions
• Class II: Other missense variants in exons 1-11, with variable effects on protein function
• Class III: Variants causing a premature stop codon, including frameshift and splicing variants, leading to truncated or non-functional proteins
• Class IV: Missense variants in the cytosolic tail, potentially altering intracellular signaling or transport mechanisms
Genotype-Phenotype Correlations:
Hanks et al., 2003 and Casas-Alba et al., 2018 have established a strong relationship between ANTXR2 variants and disease severity in HFS.
• Severe phenotype: Individuals with at least one insertion or deletion in ANTXR2, leading to a frameshift mutation, exhibited a severe disease course. These cases are marked by extreme pain with minimal handling, gingival hypertrophy, subcutaneous nodules, and progressive joint contractures. The most severe cases frequently result in early mortality due to intractable diarrhea, recurrent infections, and organ failure, with a median age of death of 15 months.
Missense variations in exons 1-12, which encode the extracellular vWA domain, and variations causing a premature stop codon are strongly associated with this life-limiting form of the disease.
• Milder phenotype: In contrast, in-frame and missense variants in the cytoplasmic domain (exons 13-17) are linked to a less severe disease course, allowing survival into adulthood and typically lacking recurrent infections, diarrhea, or multiorgan failure. However, skeletal abnormalities are variably present among affected individuals.
The cytoplasmic domain of ANTXR2 is involved in intracellular signaling and transport, and variants in this region may partially preserve protein function, leading to a milder disease phenotype.
Diagnostic Testing:
Genetic testing: Confirmation via sequence analysis of ANTXR2, followed by the deletion-duplication analysis
Histopathology: Skin biopsy revealing hyaline material accumulation
Radiographic findings: Osteopenia, periosteal reaction, and lucent lesions
Genetic Counseling:
HFS follows an autosomal recessive inheritance pattern. When both parents are carriers, each offspring has a 25% chance of inheriting the disorder, a 50% chance of being a carrier, and a 25% chance of being unaffected. Carrier testing and prenatal diagnosis are available for at-risk families.
ANTXR2