ANKH – Familial Calcium Pyrophosphate Dihydrate Deposition Disease (Chondrocalcinosis 2)

ANKH encodes a multipass membrane protein that transports inorganic pyrophosphate (PPi) from the intracellular to extracellular compartment. Familial calcium pyrophosphate dihydrate deposition disease (CPPD), designated chondrocalcinosis 2, maps to the CCAL2 locus on chromosome 5p, where ANKH mutations cluster and enhance PPi export, promoting crystal formation (PMID:15474385).

A Tunisian kindred exhibited autosomal dominant inheritance with low penetrance; 15 of 103 adult members developed radiographic chondrocalcinosis at a mean age of 59.4 years (PMID:15474392). Clinical presentations included pseudogout, pseudoosteoarthritis, and asymptomatic calcification, reflecting variable expressivity.

Segregation analysis across this and additional French and UK kindreds further supports a strong genetic component to CCAL2-associated CPPD (PMID:15474385).

Variant spectrum in ANKH includes both coding and regulatory alleles. The missense change c.1165G>C (p.Gly389Arg) mislocalizes ANKH to the cytoplasm, disrupts PPi transport, and increases extracellular mineralization in chondrocytes (PMID:32366894). An upstream regulatory substitution, c.-4G>A, enhances ANKH transcription and PPi export in vitro (PMID:15818664).

Functional studies demonstrate that gain-of-function ANKH mutations consistently elevate extracellular PPi, crystal deposition, and chondrocyte hypertrophy markers, recapitulating key disease features (PMID:15818664; PMID:32366894).

Overall, multiple unrelated families with segregating ANKH variants, combined with concordant in vitro functional data, support a Strong clinical validity for the autosomal dominant association of ANKH with chondrocalcinosis 2. Genetic testing of ANKH is recommended in familial CPPD to guide diagnosis, prognosis, and potential therapeutic targeting.

References

• Joint Bone Spine • 2004 • Familial calcium pyrophosphate dihydrate deposition disease. A Tunisian kindred. PMID:15474392
• Joint Bone Spine • 2004 • The ANKH gene and familial calcium pyrophosphate dihydrate deposition disease. PMID:15474385
• Arthritis and Rheumatism • 2005 • Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5'-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate. PMID:15818664
• Scientific Reports • 2020 • Differences in intracellular localisation of ANKH mutants that relate to mechanisms of calcium pyrophosphate deposition disease and craniometaphyseal dysplasia. PMID:32366894

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