A Mutation in the Human Glucocerebrosidase Gene in Neuronopathic Gaucher's Disease

TLDR

The study sought a genetic marker for acute neuronopathic Gaucher’s disease by comparing the glucocerebrosidase gene sequence from a patient with a normal allele. Researchers performed NciI restriction‑fragment–length polymorphism analysis on genomic DNA from 20 type 1, 5 type 2, 11 type 3 Gaucher’s patients and 29 controls to detect the mutation. A single T→C substitution in exon X creates a leucine‑to‑proline change at position 444 and an NciI site; it was found in 4/5 type 2, all 11 type 3, 2/5 type 2 and 7/11 type 3 homozygotes, 4/20 type 1 heterozygotes, and none of the controls, indicating a high frequency in neuronopathic forms and potential diagnostic value. Citation: N Engl J Med 1987; 316:570–5.

Abstract

To search for a genetic marker for type 2 Gaucher's disease (acute neuronopathic form), we compared the nucleotide sequence of a cloned glucocerebrosidase gene from a patient with Gaucher's disease with a normal gene. We found only a single base substitution (T→C) in exon X. This mutation results in the substitution of proline for leucine in position number 444 and produces a new cleavage site for the NciI restriction endonuclease. We analyzed NciI enzymatic digests of genomic DNA from 20 patients with type 1, 5 with type 2, and 11 with type 3 Gaucher's disease, and 29 normal controls for a restriction-fragment–length polymorphism (RFLP). Four of 5 patients with type 2 disease and all 11 with type 3 disease had at least one allele with the mutation. Two of 5 patients with type 2 disease and 7 of 11 with type 3 were homozygous for this mutation. Only 4 of 20 patients with type 1 Gaucher's disease had the mutant allele and were heterozygous for it. None of the 29 normal controls had the mutant allele. The high frequency of this mutation (444leucine→proline) in patients with neuronopathic Gaucher's disease, detectable by the NciI RFLP, may be of value in the identification of patients who will have the neurologic sequelae of Gaucher's disease. (N Engl J Med 1987; 316:570–5.)