Kurolap et al. (2019) noted that the ASP409HIS mutation is annotated as ASP448HIS (D448H), resulting from a c.1342G-C transversion (c.1342G-C, NM_000157.3) in the GBA gene. The sequence includes the 39-residue signal peptide.
The asp409-to-his (D409H) substitution in exon 9 of the GBA gene has also been reported as resulting from a c.957G-C transversion, based on a different reference sequence (Beutler, 1992).
Theophilus et al. (1989) identified a heterozygous D409H mutation in the GBA gene in 2 patients with type I Gaucher disease (230800) and 1 patient with type III (231000) Gaucher disease.
Cormand et al. (1995) identified heterozygosity for the D409H allele in Spanish patients with types I, II (230900), and III Gaucher disease. All patients had markedly different clinical phenotypes. Cormand et al. (1995) found that the D409H mutation accounted for 4 (5.7%) of 70 mutated alleles among 35 Spanish patients with Gaucher disease.
Chabas et al. (1995) described 3 Spanish sisters with an unusual form of Gaucher disease, later designated type IIIC (231005) (Bohlega et al., 2000), due to a homozygous D409H substitution in the GBA gene. Hepatosplenomegaly was present in all 3 sibs; characteristic Gaucher cells were found on bone marrow aspirate in 2 and in the splenectomy specimen in the third. The patients had cardiovascular abnormalities consisting of calcification of the ascending aorta and of the aortic and mitral valves. Neurologic findings included ophthalmoplegia and saccadic eye movements in 2 of the sisters, and tonic-clonic seizures in the third. The 3 sisters died at ages 16, 15, and 13, 2 of them having undergone aortic valve replacement.
Uyama et al. (1997) identified the homozygous D409H mutation in 3 Japanese adult sibs reported by Uyama et al. (1992) who had Gaucher disease associated with supranuclear ophthalmoplegia and cardiovascular calcifications.
Homozygosity for the D409H mutation has been reported in Arab (Abrahamov et al., 1995) and British/German (Beutler et al., 1995) patients with Gaucher disease and cardiovascular calcifications. These reports demonstrate a particularly tight pan-ethnic association between phenotype and genotype in this variant form of Gaucher syndrome.
Bohlega et al. (2000) described 4 Saudi Arabian sibs with the D409H mutation who had impaired horizontal saccades and aortic and mitral valve calcification without other systemic disease. Bohlega et al. (2000) suggested the designation 'Gaucher disease type IIIC.'
Inui et al. (2001) reported a patient who was compound heterozygous for the D409H allele and another unidentified mutation. He had hydrocephalus, corneal opacities, deformed toes, and cardiac features typical of patients who are homozygous for this allele. However, he also had fibrous thickening of the splenic and hepatic capsules and massive hepatosplenomegaly, features which differed from patients homozygous for the D409H allele. Enzyme replacement therapy was given for 4 years, resulting in an improvement of visceral and hematologic abnormalities but no neurologic improvement.
Mignot et al. (2003) identified the D409H mutation in compound heterozygosity with another mutation in a fetus with perinatal lethal Gaucher disease (608013).
Emre et al. (2008) identified homozygosity for the D409H mutation in 2 unrelated Turkish patients with Gaucher disease, who had cardiac valvular involvement and severe cardiac disease associated with hepatosplenomegaly.
