Online Mendelian Inheritance in Man (OMIM) (original) (raw)

* 609471

GLUCOSIDASE, BETA, ACID 2; GBA2

Alternative titles; symbols

BETA-GLUCOSIDASE, BILE ACID

BILE ACID BETA-GLUCOSIDASE
KIAA1605
GLUCOSYLCERAMIDASE, NONLYSOSOMAL

HGNC Approved Gene Symbol: GBA2

SNOMEDCT: 723822009;

Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38) : 9:35,736,866-35,749,228 (from NCBI)

Gene-Phenotype Relationships

TEXT

Description

The GBA2 gene encodes an enzyme initially identified as a microsomal beta-glucosidase that catalyzes the hydrolysis of endogenous bile acid 3-O-glucosides (Matern et al., 2001). The enzyme is also a nonlysosomal glucosylceramidase that catalyzes the conversion of glucosylceramide to free glucose and ceramide, as well as the reverse reaction consisting in the transfer of glucose to different lipid substrates. As an enzyme of sphingolipid metabolism, it plays a role in a variety of cell signaling responses and in structural components of the plasma membrane (summary by Martin et al., 2013).

Cloning and Expression

By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned GBA2, which they designated KIAA1605. The deduced protein contains 922 amino acids. RT-PCR ELISA detected high GBA2 expression in all adult and fetal tissues examined, with highest expression in adult heart and brain. High expression was also detected in all specific adult brain regions examined, with highest expression in substantia nigra, subthalamic nucleus, thalamus, and caudate nucleus.

By searching an EST database for sequences encoding peptide fragments obtained from purified human liver GBA2, followed by PCR and RACE of a human liver cDNA library, Matern et al. (2001) cloned GBA2. The 5-prime UTR of the transcript has a high GC content. The deduced protein contains 927 amino acids and has a calculated molecular mass of 104.6 kD. GBA2 contains a putative membrane-spanning domain and 2 potential N-glycosylation sites. However, glycosidase treatment indicated that GBA2 is not a glycoprotein. Northern blot analysis detected a 3.6-kb transcript in all tissues examined, with highest expression in brain, heart, skeletal muscle, kidney, and placenta. Lower expression was detected in liver, spleen, small intestine, and lung, and very low expression was detected in colon, thymus, and peripheral blood leukocytes.

Gene Structure

Matern et al. (2001) determined that the GBA2 gene spans about 12 kb.

Mapping

By genomic sequence analysis, Matern et al. (2001) mapped the GBA2 gene to chromosome 9.

Gene Function

Boot et al. (2007) identified beta-glucosidase-2 as the nonlysosomal glucosylceramidase. The GBA2 gene was chosen as a candidate for nonlysosomal glucosylceramidase because it is a glycosyl hydrolase. Cloning and expression of the GBA2 gene in COS cells showed that it was identical to nonlysosomal glucosylceramidase in various enzymatic features, such as substrate specificity and inhibitor sensitivity. GBA2-targeted RNA interference reduced endogenous nonlysosomal glucosylceramidase activity in cells. GBA2 was found to be located at or close to the cell surface, and its activity was linked to sphingomyelin generation. Boot et al. (2007) discussed the distinction of GBA2 from lysosomal GBA (606463), mutation in which causes Gaucher disease (230800).

Molecular Genetics

In 11 patients from 4 unrelated families with autosomal recessive hereditary spastic paraplegia-46 (SPG46; 614409), Martin et al. (2013) identified 4 different biallelic mutations in the GBA2 gene (609471.0001-609471.0004). Three of the mutations were truncating and 1 was a missense mutation that was shown to result in complete loss of enzyme function. The mutations were found by exome sequencing of the candidate region identified by linkage analysis. The phenotype was characterized by early onset of progressive spastic paraparesis, cerebellar ataxia, mental impairment, cataracts, cerebral, cerebellar and corpus callosum atrophy, and infertility in males.

In 10 patients from 4 unrelated Tunisian families with autosomal recessive cerebellar ataxia and spasticity, Hammer et al. (2013) identified 3 different homozygous mutations in the GBA2 gene (609471.0005-609471.0007). The first mutations were identified by homozygosity mapping and exome sequencing. The patients presented with cerebellar ataxia in the first 2 decades of life and later developed spasticity and axonal neuropathy. Only 1 patient had mild intellectual impairment, and only 1 had an abnormal brain MRI.

Animal Model

Yildiz et al. (2006) generated Gba2-knockout mice and found that they had normal bile acid metabolism; however, males exhibited impaired fertility and had globozoospermia with abnormal acrosomes and defective mobility. Glucosylceramides accumulated in the testes, brains, and livers of the Gba2-knockout mice but did not cause obvious neurologic symptoms, organomegaly, or reduction in life span. In GBA2-transfected simian COS and human embryonic kidney cells, the authors demonstrated that GBA2 hydrolyzes glucosylceramide to glucose and ceramide. Yildiz et al. (2006) concluded that GBA2 is a glucosylceramidase, the loss of which causes accumulation of glycolipids and an endoplasmic reticulum storage disease.

Martin et al. (2013) found that morpholino knockout of Gba2 in zebrafish induced a curly tail phenotype in 12.5% of morphants, but 73.8% had no visible abnormalities. However, 24% of those that appeared normal showed significant motility defects compared to control embryos. These defects were associated with abnormal development of spinal motoneurons and defects in axonal outgrowth. Some of these defects could be rescued when coexpressed with wildtype human GBA2.

ALLELIC VARIANTS 8 Selected Examples):

.0001 SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE

GBA2, ARG630TRP
SNP: rs398123012, gnomAD: rs398123012, ClinVar: RCV000034369, RCV000515985

In affected members of a large consanguineous Tunisian family with autosomal recessive hereditary spastic paraplegia-46 (SPG46; 614409), Martin et al. (2013) identified a homozygous 1888C-T transition in exon 12 of the GBA2 gene, resulting in an arg630-to-trp (R630W) substitution at a highly conserved residue in the six-hairpin-glucosidase-like domain of the enzyme. The mutation, which segregated with the disorder and was not found in 1,038 control chromosomes or 6,500 control exomes, was found by sequencing all coding exons in the region on chromosome 9 identified by linkage analysis (Boukhris et al., 2010). Direct sequencing of the GBA2 gene in 95 probands with autosomal recessive SPG identified a homozygous R630W substitution in a Portuguese patient with the disorder whose parents were related. Each unaffected parent was heterozygous for the mutation. The mutation-carrying haplotypes differed between the 2 families. Cells from the Portuguese patient showed a complete lack of GBA2 activity, and in vitro functional expression studies showed that the mutant enzyme had no GBA2 activity, consistent with a complete loss of function. Morpholino knockout of the Gba2 gene in zebrafish resulted in variable curly tail, motility defects, abnormal development of spinal motoneurons, and defects in axonal outgrowth. Coexpression of the R630W mutant protein could not rescue these defects, although wildtype human GBA2 could rescue the defects.

.0002 SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE

GBA2, ARG234TER
SNP: rs398123013, gnomAD: rs398123013, ClinVar: RCV000034370, RCV001268639

In 2 sibs, born of consanguineous Turkish parents, with spastic paraplegia-46 (SPG46; 614409), Martin et al. (2013) identified a homozygous 700C-T transition in exon 4 of the GBA2 gene, resulting in an arg234-to-ter (R234X) substitution. The mutation was identified by exome sequencing.

.0003 SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE

GBA2, TRP173TER
SNP: rs1588022768, ClinVar: RCV000790866

In affected members of a Belgian family with spastic paraplegia-46 (SPG46; 614409), Martin et al. (2013) identified compound heterozygosity for 2 mutations in the GBA2 gene: a 518G-A transition in exon 3, resulting in a trp173-to-ter (W173X) substitution, and a 4-bp duplication in exon 9 (1471dupGGCA; 609471.0004), resulting in a frameshift and premature termination (Thr492ArgfsTer9).

.0004 SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE

GBA2, 4-BP DUP, 1471GGCA
SNP: rs1588010939, ClinVar: RCV000034372

For discussion of the 4-bp duplication in exon 9 of the GBA2 gene (1471dupGGCA) that was found in compound heterozygous state in patients with spastic paraplegia-46 (SPG46; 614409) by Martin et al. (2013), see 609471.0003.

.0005 SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE

GBA2, ARG340TER
SNP: rs398123014, gnomAD: rs398123014, ClinVar: RCV000034373, RCV001043691

In 5 patients from 2 unrelated consanguineous Tunisian families with spastic paraplegia-46 (SPG46; 614409), Hammer et al. (2013) identified a homozygous 1018C-T transition in exon 5 of the GBA2 gene, resulting in an arg340-to-ter (R340X) substitution. The mutation, which was identified by homozygosity mapping and exome sequencing and segregated with the disorder, was not found in 50 Tunisian controls or in 330 additional controls. The patients presented in the first decade of life with cerebellar ataxia and later developed spasticity and axonal neuropathy.

.0006 SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE

GBA2, ARG873HIS
SNP: rs398123015, ClinVar: RCV000034374, RCV000515888

In 2 sibs, born of consanguineous Tunisian parents, with spastic paraplegia-46 (SPG46; 614409), Hammer et al. (2013) identified a homozygous 2618G-A transition in exon 17 of the GBA2 gene, resulting in an arg873-to-his (R873H) substitution at a highly conserved residue. The mutation, which was identified by homozygosity mapping and exome sequencing and segregated with the disorder, was not found in 50 Tunisian controls or in 330 additional controls. The patients presented in the first decade of life with cerebellar ataxia and later developed spasticity and axonal neuropathy.

.0007 SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE

GBA2, TYR121TER
SNP: rs1588023668, ClinVar: RCV000790865

In 3 Tunisian sibs, born of consanguineous Tunisian parents, with spastic paraplegia-46 (SPG46; 614409), Hammer et al. (2013) identified a homozygous 363C-A transversion in exon 2 of the GBA2 gene, resulting in a tyr121-to-ter (Y121X) substitution at a highly conserved residue. The mutation was not found in 50 Tunisian controls or in 330 additional controls. The patients presented in their teenage years with cerebellar ataxia and later developed spasticity and sensory axonal neuropathy.

.0008 SPASTIC PARAPLEGIA 46, AUTOSOMAL RECESSIVE

GBA2, ASP594HIS
SNP: rs398123064, ClinVar: RCV000077800

In 3 sibs, born of consanguineous Cypriot parents, with spastic paraplegia-46 (SPG46; 614409), Votsi et al. (2014) identified a homozygous c.1780G-C transversion in exon 11 of the GBA2 gene, resulting in an asp594-to-his (D594H) substitution at a highly conserved residue in the 6-hairpin glycosidase-like domain. Two other homozygous variants in GBA2 also segregated with the disorder: c.2054+62G-A in intron 13, and c.2201G-A in exon 15, resulting in an arg734-to-his (R734) substitution; these 2 variants, however, were also found in controls and were not considered to be pathogenic. The mutations were found by homozygosity mapping combined with whole-exome sequencing and candidate gene analysis and were confirmed by Sanger sequencing. D594H was not found in 264 control Cypriot chromosomes. The patients presented with mixed features of cerebellar ataxia and spasticity with onset in the second decade of life. Functional studies of the variants were not performed.

REFERENCES

1. Boot, R. G., Verhoek, M., Donker-Koopman, W., Strijland, A., van Marle, J., Overkleeft, H. S., Wennekes, T., Aerts, J. M. F. G.Identification of the non-lysosomal glucosylceramidase as beta-glucosidase 2. J. Biol. Chem. 282: 1305-1312, 2007. [PubMed: 17105727] [Full Text: https://doi.org/10.1074/jbc.M610544200\]
2. Boukhris, A., Feki, I., Elleuch, N., Miladi, M. I., Boland-Auge, A., Truchetto, J., Mundwiller, E., Jezequel, N., Zelenika, D., Mhiri, C., Brice, A., Stevanin, G.A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum. Neurogenetics 11: 441-448, 2010. [PubMed: 20593214] [Full Text: https://doi.org/10.1007/s10048-010-0249-2\]
3. Hammer, M. B., Eleuch-Fayache, G., Schottlaender, L. V., Nehdi, H., Gibbs, J. R., Arepalli, S. K., Chong, S. B., Hernandez, D. G., Sailer, A., Liu, G., Mistry, P. K., Cai, H., Shrader, G., Sassi, C., Bouhlal, Y., Houlden, H., Hentati, F., Amouri, R., Singleton, A. B.Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am. J. Hum. Genet. 92: 245-251, 2013. [PubMed: 23332917] [Full Text: https://doi.org/10.1016/j.ajhg.2012.12.012\]
4. Martin, E., Schule, R., Smets, K., Rastetter, A., Boukhris, A., Loureiro, J. L., Gonzalez, M. A., Mundwiller, E., Deconinck, T., Wessner, M., Jornea, L., Oteyza, A. C., and 10 others.Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am. J. Hum. Genet. 92: 238-244, 2013. [PubMed: 23332916] [Full Text: https://doi.org/10.1016/j.ajhg.2012.11.021\]
5. Matern, H., Boermans, H., Lottspeich, F., Matern, S.Molecular cloning and expression of human bile acid beta-glucosidase. J. Biol. Chem. 276: 37929-37933, 2001. [PubMed: 11489889] [Full Text: https://doi.org/10.1074/jbc.M104290200\]
6. Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O.Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 273-281, 2000. [PubMed: 10997877] [Full Text: https://doi.org/10.1093/dnares/7.4.271\]
7. Votsi, C., Zamba-Papanicolaou, E., Middleton, L. T., Pantzaris, M., Christodoulou, K.A novel GBA2 gene missense mutation in spastic ataxia. Ann. Hum. Genet. 78: 13-22, 2014. [PubMed: 24252062] [Full Text: https://doi.org/10.1111/ahg.12045\]
8. Yildiz, Y., Matern, H., Thompson, B., Allegood, J. C., Warren, R. L., Ramirez, D. M. O., Hammer, R. E., Hamra, F. K., Matern, S., Russell, D. W.Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility. J. Clin. Invest. 116: 2985-2994, 2006. [PubMed: 17080196] [Full Text: https://doi.org/10.1172/JCI29224\]

Contributors:

Cassandra L. Kniffin - updated : 1/7/2014
Cassandra L. Kniffin - updated : 4/3/2013
Marla J. F. O'Neill - updated : 11/30/2006

Creation Date:

Patricia A. Hartz : 7/12/2005

Edit History:

mcolton : 02/10/2015
carol : 1/8/2014
ckniffin : 1/7/2014
carol : 9/24/2013
carol : 4/4/2013
ckniffin : 4/3/2013
wwang : 6/6/2007
wwang : 11/30/2006
mgross : 7/12/2005