Gaucher disease as a paradigm of current issues regarding single gene mutations of humans.

Abstract

Gaucher disease is a glycolytic storage disease caused by a deficiency in activity of the catabolic enzyme glucocerebrosidase. Over 35 different mutations have been documented, including missense and nonsense point mutations, splicing mutations, deletions and insertions, a fusion gene, and examples of gene conversion. Gaucher disease is most common in the Ashkenazi Jewish population, in which just five of the mutations in this population account for 98% of the disease-producing alleles. Each of these mutations is found in the context of a single haplotype, a finding consistent with a single origin of each mutation. Although it is clear that these mutations provide a selective advantage in the Jewish population and thus constitute a balanced polymorphism, the nature of the advantage is unknown. Gaucher disease can be treated symptomatically, by administration of the missing enzyme, by allogeneic bone marrow transplantation, and potentially by gene transfer into hematopoietic stem cells. Increasing understanding of this disease has, as in other genetic disorders, created a host of social and ethical dilemmas regarding matters such as the cost of treatment for rare diseases and the advantages and disadvantages of population-targeted genetic screening.

Consequences of diagnostic delays in type 1 Gaucher disease: The need for greater awareness among Hematologists–Oncologists and an opportunity for early diagnosis and intervention

“…Of GD patients registered in the International Collaborative Gaucher Group (ICGG) database, 11% and 55% of the non-Jewish and Jewish population are homozygous for the N370S mutation, respectively [13]. This genotype is believed to have low expressivity and one estimate indicates that nearly two-thirds never come to medical attention [14]. Gaucher patients homozygous for N370S appear to be at elevated risk for disabling complications resulting from diagnostic delays.…”

Gaucher disease: expression and characterization of mild and severe acid β-glucosidase mutations in Portuguese type 1 patients

“…12,15 Screening for four mutations (N370S, L444P, G377S and N396T) in the Portuguese population, where type 1 GD is the most prevalent lysosomal storage disease (being some 25 times more frequent than the neuronopathic forms), detected 85% of mutant or about 15% unknown alleles. 27 In this communication , three new mutations (F109V, W184R, R395P) and three previously reported but uncharacterized lesions (R359Q, 28 G377S, 29 N396T 12 ) were detected in 12 Portuguese patients with type 1 GD.…”

“…However, genotype/ phenotype correlations have been possible for the most frequently identified mutations, N370S and L444P. 7,[14][15][16][17][18] The presence of at least one N370S allele precludes development of neurological manifestations, even if the heteroallele is completely inactive; 19,20 and homoallelism for the L444P mutation is generally predictive of neurological disease. [21][22][23][24] Nonetheless, significant phenotypic variability occurs within the subtypes, 25,26 and in particular within type 1 GD, as illustrated by patients homoallelic for the N370S allele, whose condition, although primarily mild, can range from clinically asymptomatic to severely involved with massive hepatosplenomegaly and debilitating bone disease.…”

Murine MHC class II locus control region drives expression of human β-glucocerebrosidase in antigen presenting cells of transgenic mice

“…Different point mutations, insertional mutations, deletions and splicing mutations in the ␤-glucocerebrosidase gene have been described, which lead to the heterogeneity of clini-cal lesions. 5 There is a relationship between the type of mutation and the clinical manifestation of the disease 6,7 but there is also some degree of variability among patients with the same disease genotype. 5 Current treatment for most Gaucher patients is still supportive and symptomatical, dealing with clinical manifestations (hepatosplenomegaly, anaemia, osseous lesions, fibrosis, cirrhosis etc) rather than with the cause of the disease.…”

“…5 There is a relationship between the type of mutation and the clinical manifestation of the disease 6,7 but there is also some degree of variability among patients with the same disease genotype. 5 Current treatment for most Gaucher patients is still supportive and symptomatical, dealing with clinical manifestations (hepatosplenomegaly, anaemia, osseous lesions, fibrosis, cirrhosis etc) rather than with the cause of the disease. Other available options are enzyme replacement therapy, 8,9 allogenic bone marrow transplantation 10,11 and, potentially, somatic gene therapy by gene transfer into haematopoietic stem cells (HSCs).…”