NT5E – hereditary arterial and articular multiple calcification syndrome

Calcification of joints and arteries (CALJA), also known as hereditary arterial and articular multiple calcification syndrome, is an autosomal recessive ectopic mineralization disorder characterized by late-onset calcification of peripheral arteries and joint capsules. NT5E encodes CD73, a glycosylphosphatidylinositol-anchored ecto-5'-nucleotidase that converts AMP to adenosine. Biallelic NT5E loss-of-function variants were first identified in three families with symptomatic lower-extremity arterial and hand/foot joint capsule calcifications, including homozygous nonsense c.662C>A (p.Ser221Ter), missense c.1073G>A (p.Cys358Tyr), and frameshift c.1608dup (p.Val537fs) variants ([PMID:21288095]).

Subsequent reports have expanded the genetic and phenotypic spectrum to >26 probands across at least 13 unrelated families, all with autosomal recessive inheritance ([PMID:26178434], [PMID:33744914], [PMID:32522903], [PMID:34999808]). The NT5E variant spectrum includes loss-of-function alleles (nonsense, frameshift, splice: c.751+2T>C) and pathogenic missense substitutions (c.1360G>A (p.Gly454Arg), c.1510G>C (p.Gly504Arg), c.3G>C (p.Met1Ile)) distributed throughout the catalytic domain.

Segregation analysis in large pedigrees demonstrated cosegregation of biallelic NT5E variants with CALJA: five affected siblings in Family 1, three in Family 2, and multiple affected relatives in Japanese and Chinese kindreds, yielding segregation in 10 additional family members with confirmed genotypes ([PMID:21288095], [PMID:33744914]).

Functional studies support a loss-of-function mechanism. Protein structural modeling indicated the p.Gly454Arg change disrupts β-pleated sheet folding ([PMID:26178434]). In vitro expression of mutant NT5E in COS-7 cells revealed intracellular retention and absent ecto-5'-nucleotidase activity ([PMID:24887587]). Patient fibroblasts lack CD73 activity, accumulate calcium phosphate crystals and elevated alkaline phosphatase levels, all of which are rescued by wild-type NT5E expression or adenosine supplementation ([PMID:21288095]).

Phenotypic expansion includes upper-extremity arterial calcification, multifocal periarticular hydroxyapatite deposition, chronic limb-threatening ischemia, late-onset aortic stenosis, and erosive arthropathy. Radiological and histochemical analysis of synovial biopsies confirmed calcium pyrophosphate and hydroxyapatite crystals in affected joints ([PMID:33744914], [PMID:32522903], [PMID:34999808]).

Integration of genetic and experimental data indicates that biallelic NT5E variants cause CALJA via CD73 deficiency and impaired adenosine-mediated inhibition of tissue mineralization. NT5E sequencing is recommended for patients with unexplained arterial or periarticular calcifications to enable accurate diagnosis, genetic counseling, and targeted management.

References

• The New England journal of medicine • 2011 • NT5E mutations and arterial calcifications PMID:21288095
• Journal of human genetics • 2015 • Calcification of joints and arteries: second report with novel NT5E mutations and expansion of the phenotype. PMID:26178434
• Rheumatology (Oxford, England) • 2021 • Multifocal calcific periarthritis with distinctive clinical and radiological features in patients with CD73 deficiency. PMID:33744914
• Circulation journal : official journal of the Japanese Circulation Society • 2020 • NT5E Genetic Mutation Is a Rare But Important Cause of Intermittent Claudication and Chronic Limb-Threatening Ischemia. PMID:32522903
• Interactive cardiovascular and thoracic surgery • 2022 • NT5E mutation in sisters who underwent aortic valve replacements for aortic stenosis. PMID:34999808
• PLoS one • 2014 • NT5E mutations that cause human disease are associated with intracellular mistrafficking of NT5E protein. PMID:24887587

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