Abstract # 290 A Heterozygous Mutation in the Human ANK Gene in a British Family with Adult Onset Chondrocalcinosis due to Calcium Pyrophosphate Crystal Deposition. A. Pendleton, M. Johnston, A. Ho, K. Gurley, et al. Belfast, Nottingham, UK; Stanford, CA.

Abstract # 654 Analysis of the ANK Gene Reveals a Heterozygous Missense Mutation in a French Family with Calcium Pyrophosphate Deposition Disease. M. Johnson, A Ho, R. McGrath, P Netter et al. Stanford; Philadelphia; Nancy, France and Camden.

Abstract # 655 Characterization of Sequence Variants in ANK in Familial Calcium Pyrophosphate Deposition Disease. S. Pearlso, R. McGrath, G. Bonavita, A. Reginato, et al. Phildelphia; Camden; Cordoba, Argentina and Bogota, Columbia.

This group of studies examined the role of the human ANK gene in familial calcium pyrophosphate disease (CPPD). Familial chondrocalcinosis (CC) has been linked to a region on chromosome 5p. A gene called ANK that regulates cellular transport of pyrophosphate in mice was described recently, and has a human ortholog that maps to the 5p chromosome region.

In the study of Pendleton et al, a heterozygous Guanine to Adenine base change was identified in all of the affected individuals within the kindred and was not found in the unaffected members of the family or in 100 unaffected controls. This base substitution created a new ATG initiation codon upstream from the original start codon. Reconstruction of the mutation showed that the new ATG sequence is recognized as a translational start, that leads to the production of a novel ANK protein that is 344 daltons larger than normal. The mutation thus alters the translation and sequence of the highly conserved ANK protein.

In the second study by Johnson et al, a heterozygous base substitution in exon 2 that changed a Methoionine to Threonine at position 48 was found. The M to T sequence variant completely segregated with the disease phenotype in the family, and analysis of 200 alleles from control subjects did not reveal this missense mutation. The sequence variant at position 48 did not appear, however, to significantly alter primary or secondary structural parameters of the ANK protein. The mutation was in a highly conserved area of the protein.

In the third study by Peariso et al, a group of five families was studied. Numerous sequence variants were detected, including exon and intron SNPs, as well as a SNP in the 5 UTR region of the gene. There was, however, no evidence for major gene deletion, insertion or re-arrangement, and analyses of expression levels for ANK in these families was unremarkable.

Conclusion:It remains unclear from these studies if a mutation in the human ANK gene is indeed responsible for familiar CPPD. The first study is the most supportive of the concept, though the investigators will have to prove that the larger mutant ANK protein is, in some way, dysfunctional compared to native ANK.

Editorial Comment: The ANK protein is a transmembrane protein (presumably a channel) that is involved in the transport of pyrophosphate (PPi) from intracellular compartments to the extracellular space. Extracellular PPi antagonizes the ability of inorganic phosphate (Pi) to crystallize with calcium to form hydroxyapatite. Mice with ANK deficiency develop diffuse calcification and hyperostosis that resembles ankylosing spondylitis. These mice have significant decreases in plasma and extracellular PPi levels. Administration of the PPi analogue phosphocitrate to ANK/ANK mice suppresses the development of hyperostosis.

The studies presented in these abstracts are the first attempts to demonstrate a human correlate of the ANK/ANK mouse. The second and third studies failed to find a mutation in the ANK gene that correlated with an aberrant protein. The first study identified a mutation that resulted in a larger ANK protein, but the function of the mutant protein has not yet been elucidated. One hypothesis would be that the mutant protein is less efficient in transporting PPi to the extracellular space, thereby eliminating an inhibitory control for calcification. It will be interesting to determine whether patients with ankylosing spondylitis also have ANK (or PC-1) mutations, and whether phosphocitrate or analog can inhibit these calcific and enthesopathic diseases.

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