Chitotriosidase variants in patients with Gaucher disease. Implications for diagnosis and therapeutic monitoring.
OBJECTIVE
Human plasma chitotriosidase (ChT) activity, a biomarker for evaluating and monitoring Gaucher disease (GD), varies in the general population owing to variants in the CHIT1 gene. Our aim is to determine the frequency of the c.1049_1072dup24 (dup24) and p.G102S polymorphisms, their influence on plasma ChT activity, and its change with enzyme replacement therapy (ERT).


METHODS
The study included 269 type1 GD patients. Genomic DNA was genotyped using PCR, restriction isotyping and agarose gel electrophoresis. ChT activity was measured with the 4-methylumbelliferyl-β-D-N,N',N″triacetylchitotrioside substrate at non-saturating concentrations at diagnosis, before beginning therapy and after one year on ERT.


RESULTS
Allele frequencies for dup24 and p.G102S were 0.22 and 0.27, respectively. Four percent of patients were homozygous and 37% heterozygous for dup24, and 9% homozygous and 37% heterozygous for p.G102S. The presence of dup24 and p.G102S polymorphisms in the CHIT1 gene significantly reduced plasma ChT activity in naïve patients. By contrast, the percentage of ChT activity decrease after one year of ERT was independent of the presence of these genetic variants.


CONCLUSIONS
This study indicates that genotyping for c.1049_1072dup24 and p.G102S polymorphisms will improve the interpretation of plasma chitotriosidase activity at diagnosis but, this is not mandatory for monitoring of enzyme replacement therapy.
Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Zaragoza, Spain; Instituto de Investigación Sanitaria de Aragón (IIS), San Juan Bosco 13, 50009 Zaragoza, Spain. Electronic address: mpirun@unizar.es.
P
P
Irún
P
P
Alfonso
S
S
Aznarez
P
P
Giraldo
M
M
Pocovi
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D056947:Enzyme Replacement Therapy; D005260:Female; D005776:Gaucher Disease / Q000097:blood / Q000235:genetics* / Q000628:therapy; D005787:Gene Frequency; D006579:Heterozygote; D006596:Hexosaminidases / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D011110:Polymorphism, Genetic; D013030:Spain; D055815:Young Adult
D006596:Hexosaminidases; C086400:chitotriosidase
4-methylumbelliferyl-β-D-N,N′,N″triacetylchitotrioside; 4MU-chitotrioside; CHIT1; ChT; Chitotriosidase; ERT; Enzyme replacement therapy; GD; Gaucher disease; HET102; HETdup24; HOMO102; NEG102; NEGdup24; Polymorphisms; SSI; base pairs; bp; c.1049_1072dup24; chitotriosidase; dup24; enzyme replacement therapy; eow; every other week; heterozygous for dup24; heterozygous for p.G102S; homozygous for p.G102S; negative for dup24; negative for p.G102S; severity score index