Alkaptonuria ( AKU ) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase ( HGD ) gene leading to the deficiency of HGD enzyme activity.
The DevelopAKUre project is underway to test Nitisinone ( Orfadin ) as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway.
Researchers have analysed DNA of 40 alkaptonuria patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other patients with alkaptonuria sent to the laboratory for molecular diagnostics.
Researchers have identified 12 novel DNA variants: one was identified in patients from Brazil ( c.557T>A ), Slovakia ( c.500C>T ) and France ( c.440T>C ), three in patients from India ( c.469+6T>C, c.650-85A>G, c.158G>A ), and six in patients from Italy ( c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T ).
Thus, the total number of potential alkaptonuria-causing variants found in 380 patients reported in the HGD mutation database is now 129.
Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site.
Researchers have also presented an overview of alkaptonuria in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them.
In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy. ( Xagena )
Nemethova M et al, Eur J Hum Genet 2015; Epub ahead of print