Rs421016

rs421016, also known as L444P or Leu444Pro, is a SNP causing an amino acid change in the GBA gene; it is among the most common mutations associated with Gaucher disease of any type. Amino acid predictions from genome sequence may predict this as L483P or Leu483Pro; this disparity in position calling may be due to a 39 peptide signal sequence. Polyphen 2 predicts P04062 L483P to be "possibly damaging" with a score of 0.857 (sensitivity: 0.83; specificity: 0.93). (P04062 is the uniprot ID for GBA.)

The risk allele (in current dbSNP orientation) is (G), and as the inheritance is autosomal recessive, individuals must either be compound heterozygotes (for two different GBA mutations) or rs421016(G;G) homozygotes to develop Gaucher disease. There are over 300 mutations now known to occur in the GBA gene, with many associated with increasing risk for either type I, II, or III Gaucher disease.

This SNP (along with others associated with Gaucher disease) is studied extensively in Ashkenazi Jewish populations where it is found in relatively high frequency.

Note: this SNP used to have a "mirror" SNP, rs35095275, representing the opposite strand yet the same exact nucleotide position; it has now been merged into this SNP.

One copy of rs421016(G) has also been shown to increase the risk of Parkinson's disease ~5 fold across multiple ethnicities, and to lower a bit the age of onset of Parkinson's. In one study, the estimated age-specific risk for Parkinson's disease at 60 and 80 years of age was 4.7% and 9.1% among Gaucher disease patients, i.e. those carrying two Gaucher GBA mutations, compared with 1.5% and 7.7% among GBA mutation heterozygotes, and 0.7% and 2.1% for carriers of zero Gaucher GBA mutations, respectively. Note that these risks are pooled over multiple GBA mutations including rs421016 as well as other GBA variants.

Genotype assignment in Gaucher disease by selective amplification of the active glucocerebrosidase gene.

Complex alleles of the acid beta-glucosidase gene in Gaucher disease.

Characterization of mutations in Gaucher patients by cDNA cloning.

A mutation in the human glucocerebrosidase gene in neuronopathic Gaucher's disease.