Gaucher's disease: identification of novel mutant alleles and genotype–phenotype relationships

Abstract

A sequencing protocol for the acid beta-glucosidase (GCase) gene (GBA) was developed using a long-range PCR template. This protocol has an advantage of greater DNA yields over similar strategies. Seven Gaucher's disease patients had four novel and five other rare alleles. A non-pseudogene in-frame deletion (g.2600-2602delTAC) and a new complex mutation (null allele) were identified in Gaucher's disease type 1, i.e. the g.2600-2602delTAC deletion is associated with the non-neuronopathic variant. An F251L allele was found in a baby with the collodion skin phenotype. Three mutant alleles were identified in a single primary family with type 3. The patients' father at 45 years is healthy and is heteroallelic for the G202R and E326K alleles. Family studies indicated that E326K is in trans to G202R and L444P, and that isolated E326K is non-pathogenic in this family. A rare mutation R257Q was identified in a type 2 patient, providing an association with neuronopathic disease. A genotype L444P/L444P was noted in a 22-year-old non-neuronopathic patient. Complete gene sequencing showed a new complex allele consisting of L444P and g.7741T > C in the 3' UTR. Three additional complex alleles also involved the 3' UTR. Complete gene characterization in Gaucher's disease should allow greater insights into the correlation of specific alleles with phenotype.

Analyses of Variant Acid β-Glucosidases

“…However, compound heterozygosity with G202R/E326K and L444P/ E326K genotypes and half-normal GCase activity levels indicated that normalcy for periods of 1-4 decades can exist in the presence of an E326K allele (36). Interestingly, the E349K GCase and E326K are approximately equally spaced from the active site in the crystal structure, but E349K had much greater effects on the CRIM specific activity and other enzymic properties than did E326K.…”

“…Ϫ to ϩ). This variant has been found in phenotypically normal individuals as the heteroallele to L444P-or G202R-encoding alleles (36). The ⌬36 GCase, an in-frame codon deletion of threonine 36, could be partially purified in the presence of mixture III, and that enzyme had significant CRIM specific activity (ϳ35% of wild-type).…”

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA)

“…While initially reported as single disease-causing mutations Eyal et al, 1991], two specific alterations, c.1093G4C (E326 K) and c.1223C4T (T369 M), have been found in patients primarily in cis with other identified mutations Walker et al, 2003] and have lead to published corrections after identification of a second mutation on the same allele [Torralba et al, 2001a[Torralba et al, , 2001b. Zhao et al [2003b] reported a family in which a c.1093G4C allele was found in two unaffected individuals who carried either c.721G4A (G202R) or c.1448T4C (L444P) on their second allele. Neither of the two affected individuals in this family had the c.1093G4C alteration.…”

Characterization of neuronopathic Gaucher disease among ethnic Poles

“…Specifically, there seems to be two major expressions of this phenotype; one with major visceral involvement and a second with late-onset progressive myoclonic seizures from progressive CNS disease. This segregation of phenotypes 22 serves a useful purpose in descriptions of such phenotypes throughout the world, but a continuum of neurologic phenotypes populate the spectrum between these descriptors. 12 In the ethnic Polish population, the skeletal involvement in patients with severe visceral disease has greater similarity to that described in the Swedish population than in other groups.…”

“…The above group is similar to that described as type 3a. 22 The larger type 3 group (13 individuals) developed neurologic signs later. Supranuclear gaze paresis usually predominates; massive hepatosplenomegaly, wasting, and progressive skeletal abnormalities are characteristic.…”