The leu444-to-pro (L444P) substitution in exon 10 of the GBA gene has been reported as resulting from a 1448T-C transition (Zimran et al., 1989) and from a 6433T-C transition (Latham et al., 1990), depending upon the reference sequence cited. This mutation has alternatively been referred to as LEU483PRO (Saranjam et al., 2013).
Reczek et al. (2007) stated that the L444P mutation results in retention of GBA in the ER. They found that overexpression of the human GBA receptor, LIMP2 (SCARB2; 602257), in mouse embryonic fibroblasts rescued lysosomal targeting of GBA with the L444P mutation.
Gaucher Disease
Tsuji et al. (1987) identified the L444P substitution in the GBA gene in patients with Gaucher disease types I (230800), II (230900), and III (231000). Two of the 5 patients with type II and 7 of the 11 with type III were homozygous for this mutation, whereas 4 of 20 patients with type I Gaucher disease had this mutant allele in heterozygous state. The mutant allele was not found in 29 normal controls. The L444P substitution occurs naturally in the GBA pseudogene.
Wigderson et al. (1989) identified the L444P mutation in patients with type I, type II, and type III disease. One patient with type II disease was compound heterozygous for L444P and P415R (606463.0002). Firon et al. (1990) found the L444P mutation in both Ashkenazi Jewish and non-Jewish patients with type I Gaucher disease, but only homozygotes with this mutation had the neurologic forms type II or III.
Dahl et al. (1990) found that the Norrbottnian form of Gaucher disease (type III) in Sweden is caused by the L444P mutation.
In 3 patients with type I and 1 patient with type II Gaucher disease, Hong et al. (1990) identified a complex allele with 3 point mutations in the GBA gene (606463.0009), 1 of which was L444P.
Koprivica et al. (2000) found that homozygosity for L444P was associated with type III Gaucher disease.
Saranjam et al. (2013) reported 2 unrelated infants with severe, lethal type II Gaucher disease who were compound heterozygous for 2 mutations in the GBA gene, one of which was L444P. While the other mutation was identified in the paternal line of each patient (see, e.g., T323I, 606463.0017), the L444P allele was not detected in DNA samples from either patient's mother, suggesting that it occurred either as a result of germline mosaicism or as a de novo mutation in 1 ovum that took place during cell division. The findings had implications for genetic counseling, in that even if only 1 parent is found to be a carrier for a recessive disorder, the chance of having an affected child may not be zero. Saranjam et al. (2013) noted that the L444P change occurs at a known mutational hotspot.
Parkinson Disease
Tan et al. (2007) identified a heterozygous L444P mutation in 8 (2.4%) of 331 Chinese patients with typical Parkinson disease (168600) and none of 347 controls. The age at onset was lower and the percentage of women higher in patients with the L444P mutation compared to those without the mutation. Tan et al. (2007) noted that the findings were significant because Gaucher disease is extremely rare among the Chinese.
Gutti et al. (2008) identified the L444P mutation in 4 (2.2%) of 184 Taiwanese patients with PD. Six other GBA variants were identified in 1 patient each, yielding a total of 7 different mutations in 10 patients (5.4%). Gutti et al. (2008) suggested that sequencing the entire GBA gene would reveal additional variant that may contribute to PD.
Neumann et al. (2009) identified a heterozygous L444P mutation in 11 (1.39%) of 790 British patients with PD, which was not found in 257 controls.
Gonzalez-del Rincon et al. (2013) identified a heterozygous L444P mutation in 7 (5.5%) of 128 Mexican Mestizo patients with early-onset PD (before 45 yeras of age) and in none (0%) of 252 ethnically matched controls. Six (85.7%) of the 7 patients had psychiatric symptoms, including major depressive disorder, generalized anxiety disorder, and obsessive compulsive disorder, which was significantly higher than the prevalence of these disorders in controls (24.7%). In addition, 57% of mutation carriers presented with cognitive decline compared to 5.7% of controls. Gonzalez-del Rincon et al. (2013) concluded that the risk for PD conferred by GBA mutations may be higher than previously thought, and that GBA-associated PD may predispose to psychiatric symptoms.
Lewy Body Dementia
Mata et al. (2008) identified heterozygosity for the L444P mutation in 10 (1.4%) of 721 PD patients, 1 (1.8%) of 57 patients with Lewy body dementia (DLB; 127750), and 0 of 554 control individuals, all of European origin. Mata et al. (2008) estimated that the population-attributable risk for GBA mutations in Lewy body disorders was only about 3% in patients of European ancestry.
