Type 1 Gaucher disease: Null and hypornorphic novel chitotriosidase mutations - Implications for diagnosis and therapeutic monitoring

Human plasma chitotriosidase (Chito) is a useful diagnostic and therapeutic biomarker for Type 1 Gaucher disease (GD). However, ∼40% of Caucasians are heterozygous or homozygous for a common null mutation, c.1049_1072dup24 (dup24) in the chitotriosidase gene (chitinase 1, CHIT1), that complicates interpretation for heterozygotes and precludes use for null homozygotes. 320 Type 1 GD patients were screened for CHIT1 genotype and plasma Chito enzyme levels; 37% were heterozygous and 4% were homozygous for the CHIT1 dup24 allele. Four patients who had no or very low plasma Chito activities had wild-type (wt)/dup24 or wt/wt CHIT1 genotypes, suggesting the presence of other mutations. Sequencing their CHIT1 genes revealed three novel mutations: p.E74K (E74K), p.G102S (G102S), and a complex exon 10 lesion (c.[1060G > A; 1155G > A; 1156 + 5_1156 + 8delGTAA], p.[G354R; L385L; missplicing], designated "complex E/I-10"). The G102S mutation was common in Type 1 GD patients and controls (∼30% of alleles). In contrast, the E74K mutation was rare, present only in three Type 1 GD patients (∼1% of alleles), all of Ashkenazi Jewish (AJ) descent, but it was not found in normal controls. The complex E/I-10 mutation occurred in two Caribbean Hispanic/African Type 1 GD patients and was present in 0 to 6% of alleles among normal controls from different populations. In vitro expression demonstrated that the E74K and G102S alleles had 51% and 23% of wild-type Chito catalytic efficiency, respectively. Expression of the G354R allele alone or with the L385L silent substitution did not produce detectable Chito activity or protein. RNA studies indicated that the complex E/I-10 allele also caused missplicing. Recognition of these mutations, particularly G102S, will facilitate the use and interpretation of plasma Chito activities for disease diagnosis, estimating disease severity, and monitoring therapeutic efficacy in GD.