Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: GLB1
SNOMEDCT: 18756002, 238026007, 238027003, 238044004; ICD10CM: E76.211;
Cytogenetic location: 3p22.3 Genomic coordinates (GRCh38) : 3:32,961,108-33,097,146 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p22.3 | GM1-gangliosidosis, type I | 230500 | Autosomal recessive | 3 |
| GM1-gangliosidosis, type II | 230600 | Autosomal recessive | 3 | |
| GM1-gangliosidosis, type III | 230650 | Autosomal recessive | 3 | |
| Mucopolysaccharidosis type IVB (Morquio) | 253010 | Autosomal recessive | 3 |
The GLB1 gene encodes beta-galactosidase-1 (EC 3.2.1.23), a lysosomal hydrolase that cleaves the terminal beta-galactose from ganglioside substrates and other glycoconjugates (Yoshida et al., 1991). Beta-galactosidase also occurs in a complex with neuraminidase (NEU1; 608272) and protective protein/cathepsin A (CTSA; 613111), which is a component of certain cell surface receptors (Hinek, 1996).
See also galactosylceramidase (GALC; 606890) (EC 3.2.1.46), a genetically distinct beta-galactosidase that is involved in the catabolism of other lipid compounds.
Oshima et al. (1988) isolated a cDNA corresponding to the GLB1 gene from a human placenta cDNA library. The deduced 677-residue protein has a calculated molecular mass of 75 kD and contains a putative 23-residue signal sequence and 7 potential asparagine-linked glycosylation sites.
Morreau et al. (1989) showed that the GLB1 gene gives rise to 2 alternatively spliced mRNAs: a major 2.5-kb transcript that encodes the classic lysosomal form of the enzyme of 677 amino acids, and a minor 2.0-kb transcript that encodes a beta-galactosidase-related protein (S-Gal) of 546 amino acids with no enzymatic activity and a different subcellular localization. Exons 3, 4, and 6 are deleted in the 2.0-kb mRNA because of alternative splicing of the pre-mRNA. The only difference between the 2 proteins resides in a stretch of 32 amino acids that is encoded by a different reading frame of exon 5.
Hinek (1996) and Privitera et al. (1998) found that the short beta-galactosidase-related protein of 67 kD (S-Gal) was identical to the elastin-binding protein (EBP), a major component of the nonintegrin cell surface receptor complex expressed in fibroblasts, smooth muscle cells, chondroblasts, leukocytes, and certain cancer cell types. EBP, which is localized in the endosomal compartment, binds tropoelastin (see 130160) intracellularly and functions as a molecular chaperone facilitating the secretions of tropoelastin and its assembly into elastic fibers. EBP is not a transmembrane protein, but immobilizes on the cell surface by an association with neuraminidase and PPCA. EBP binds to matrix ligands only in the absence of galactosugars, because binding of carbohydrate moieties results in a conformational change that releases the protein from the cell surface.
The GLB1 gene spans 62.5 kb and contains 16 exons (Oshima et al., 1988; Santamaria et al., 2007).
By somatic cell hybridization, Shows et al. (1978) and Shows et al. (1979) localized the beta-galactosidase gene to chromosome 3. The authors used a species-specific antiserum to human liver beta-galactosidase with an acid pH optimum to determine the chromosome assignment in man-mouse somatic cell hybrids.
Sips et al. (1985) concluded that the structural gene for beta-galactosidase maps to chromosome 3. Takano and Yamanouchi (1993) used fluorescence in situ hybridization to assign the gene to 3p21.33.
By studying recombinant inbred strains of mice, Naylor et al. (1982) found that aminoacylase-1 (ACY1; 104620) and GLB1 are 10.7 map units apart on mouse chromosome 9. Since transferrin (TF; 190000) is closely linked to these 2 loci in the mouse, they suggested that the human transferrin gene is also on chromosome 3, which is known to carry ACY1 and GLB1.
GM1-Gangliosidosis
Yoshida et al. (1991) and Nishimoto et al. (1991) independently identified mutations in the GLB1 gene in Japanese patients with various forms of GM1-gangliosidosis. Those with the infantile form (GM1G1; 230500) had specific mutations (611458.0001; 611458.0002; 611458.0005-611458.0007). Residual enzyme activity in these patients ranged from 0.65 to 1.58% of control values (Yoshida et al., 1991). Those with the late infantile/juvenile form (GM1G2; 230600) had a different mutation (R201C; 611458.0003) with residual enzyme activity ranging from 2.65 to 3.05% of control values. Those with the adult/chronic form (GM1G3; 230650) again had different mutations (611458.0004; 611458.0008) with residual enzyme activity ranging from 4.24 to 7.28% of control values. The findings indicated an inverse correlation between disease severity and residual enzyme activity.
In a patient with late-infantile GM1-gangliosidosis, Caciotti et al. (2003) identified compound heterozygosity for 2 mutations in the GLB1 gene (611458.0003; 611458.0022).
In several Italian patients with infantile GM1-gangliosidosis with cardiac involvement (see 230500), Morrone et al. (2000) identified homozygous mutations in the GLB1 gene (611458.0023-611458.0026). All of these mutations were located in the GLB1 region common to the lysosomal protein and the EBP and were shown to impair elastogenesis (Hinek et al., 2000).
Santamaria et al. (2007) identified 22 different GLB1 mutations, including 14 novel mutations, in 19 unrelated patients with GM1-gangliosidosis from south America, mainly Argentina. The vast majority had the type I phenotype. R59H (611458.0023) was the most common mutation, accounting for 15.8% (6 of 38) mutant alleles. Two unrelated patients of Gypsy origin were homozygous for this mutation.
Bidchol et al. (2015) reported molecular findings in 46 Indian patients with GM1-gangliosidosis and 2 pairs of Asian Indian parents who had carrier testing for GM1. Thirty-three different mutations in the GLB1 gene were identified; 20 of the mutations were novel, including 12 missense, 4 splicing, 3 indels, and 1 nonsense. The most common mutations were c.75+2insT (14% of alleles) and L337P (10% of alleles). None of the novel mutations were observed in the dbSNP or 1000 Genomes Project databases. Forty-one of the patients had homozygous mutations, 25 of whom were born to consanguineous parents. Thirty-two of the patients had GM1-gangliosidosis type I, 13 had GM1-gangliosidosis type II, and 1 had GM1-gangliosidosis type III. No genotype-phenotype correlation was observed.
In a 5-year-old Emirati boy, born to consanguineous parents, with GM1-gangliosidosis type I, Mohamed et al. (2020) identified a homozygous mutation in the GLB1 gene (D151Y; 611458.0029). Testing in patient fibroblasts showed less than 1% residual beta-galactosidase enzyme activity. Immunofluorescence staining in patient fibroblasts demonstrated that the mutant protein was improperly trafficked and processed, resulting in trapping in the endoplasmic reticulum (ER). Enzyme function in the fibroblasts was partially rescued by the presence of glycerol, which acts as a chemical chaperone to rescue misfolded proteins retained in the ER, or reduced temperature, which assists with conformational rescue of misfolded proteins.
Pseudodeficiency Alleles
'Pseudodeficient enzyme activity' refers to situations in which individuals show greatly reduced enzyme activity without pathologic or clinical features. Proper identification of these variants is important for accurate genetic counseling. Gort et al. (2007) found that a clinically unaffected father of a patient with GM1-gangliosidosis had decreased GLB1 enzyme activity. Genetic analysis showed that he was compound heterozygous for a truncating mutation, found in his affected child, and an arg595-to-trp (R595W) substitution, which was not found in his affected child. Functional expression analysis showed that the R595W-mutant protein had 33 to 59% residual activity. The family originated from the Basque country of Spain. The R595W polymorphism was detected in 3.2% of Basque controls and 0.8% of non-Basque controls.
Mucopolysaccharidosis Type IVB (Morquio Syndrome B)
In 3 affected individuals from 2 unrelated families with mucopolysaccharidosis type IVB (MPS4B; 253010), Oshima et al. (1991) identified compound heterozygosity for 2 mutations in the GLB1 gene (611458.0009-611458.0011).
Paschke et al. (2001) performed mutation analyses of the GLB1 gene in 17 juvenile and adult patients from various European regions with acid beta-galactosidase deficiency and skeletal abnormalities. Fifteen of these had the Morquio B phenotype and had remained neurologically healthy, whereas the other 2 exhibited psychomotor retardation of juvenile onset. The W273L mutation (611458.0009) was present in 14 of the 15 Morquio B patients. The Morquio phenotype was also expressed in compound heterozygotes for W273L and alleles typically found in GM1-gangliosidosis. One French patient with Morquio B syndrome was compound heterozygous for 2 mutations (Q408P; 611458.0021 and T500A; 611458.0020).
Caciotti et al. (2021) reported the GLB1 mutations in 9 patients, including 2 sib pairs, with MPS IVB. The mutations were identified by Sanger sequencing of the gene. Heterozygosity for the W273L (611458.0009) mutation was identified in 7 patients. Three novel mutations were identified, including a splicing mutation (611458.0027) and 2 missense mutations, V677G (611458.0028) and Y192C. In 1 patient (patient 7), only a single mutation (W273L) was identified; however, a potential splicing defect excluding exons 2-7 was identified in this patient, leading Caciotti et al. (2021) to hypothesize that a deep intronic mutation was also present.
Hinek et al. (2000) performed functional expression studies on several GLB1 mutations resulting in Morquio B disease (see, e.g., G438E, 611458.0018, T500A, W273L, and R482H, 611458.0010). All mutations were located in the coding region common to the lysosomal enzyme and the S-Gal/EBP protein, and none of the mutant proteins expressed EBP. In addition, studies of nonsense mutations in GM1-gangliosidosis with cardiac involvement (see, e.g., R351X, 611458.0019) that resulted in impairment of both protein regions also showed no EPB expression. Functional studies indicated that the Morquio syndrome B mutant and the cardiac involvement mutants showed impaired secretion of tropoelastin and did not assemble elastic fibers, resulting in impaired elastogenesis. In these mutants, coculturing with Chinese hamster ovary cells transfected with S-Gal cDNA resulted in improved deposition of elastic fibers. In contrast, cells from patients with missense mutations resulting in lysosomal beta-galactosidase deficiency, but not in S-Gal deficiency, assembled normal elastic fibers. The study validated functional roles of S-Gal in elastogenesis and elucidated an association between impaired elastogenesis and the development of connective tissue disorders in patients with Morquio B disease and in patients with infantile GM1-gangliosidosis with cardiac involvement. Thus, these disorders could be considered a 'secondary elastinopathy' (Urban and Boyd, 2000).
O'Brien et al. (1990) performed allogeneic bone marrow transplantation early in life in a case of canine GM1-gangliosidosis. Despite successful engraftment, no benefit was found.
Prieur et al. (1991) described GM1-gangliosidosis in sheep in which deficiency of beta-galactosidase was coupled with a deficiency of alpha-neuraminidase. Skelly et al. (1995) described a new form of ovine GM1-gangliosidosis in which there was a specific deficiency of lysosomal beta-D-galactosidase only.
Hahn et al. (1997) generated a mouse model lacking a functional beta-galactosidase gene by homologous recombination and embryonic stem cell technology. Tissues from affected mice were devoid of beta-galactosidase mRNA and totally deficient in GM1-ganglioside-hydrolyzing capacity. Storage material was already conspicuous in the brain at 3 weeks. By 5 weeks, extensive storage of periodic acid Schiff-positive material was observed in neurons throughout the brain and spinal cord. Consistent with the neuropathology, abnormal accumulations of GM1-ganglioside in the brain progressed from twice to almost 5 times the normal amount during the period from 3 weeks to 3.5 months. Despite accumulation of brain GM1-ganglioside at the level equal to or exceeding that seen in gravely ill human patients, these mice showed no overt clinical phenotype up to 4 to 5 months. However, tremor, ataxia, and abnormal gait became apparent in older mice.
Tohyama et al. (2000) crossbred 'twitcher' mice (galactosylceramidase deficiency; 245200) with Glb1 knockout mice and found that the acid beta-galactosidase gene dosage exerted an unexpected and paradoxical influence on the twitcher phenotype. Twitcher mice with an additional complete deficiency of Glb1 (Galc-/-, Glb1-/-) had the mildest phenotype among twitcher mice of all genotypes, with the longest life span and nearly rescued central nervous system pathology. In contrast, twitcher mice with a single functional acid beta-galactosidase gene (Galc-/-, Glb1+/-) had the most severe disease, with the shortest life span and brain levels of psychosine even higher than those of twitcher mice. The double knockout mice showed a massive accumulation of lactosylceramide in all tissues as expected, but only a half-normal amount of galactosylceramide in brain. The authors hypothesized that the acid beta-galactosidase gene may function as a modifier gene for the phenotypic expression of galactosylceramidase deficiency.
Portuguese water dogs have a naturally occurring GM1-gangliosidosis that resembles the human disease genetically, clinically, biochemically, and pathologically. It is similar to human infantile and juvenile forms of the disorder. Wang et al. (2000) isolated and sequenced the beta-galactosidase cDNA in Portuguese water dogs. The gene encodes a deduced protein of 668 amino acids. Its coding sequence is 86.5% identical at the nucleotide level and 81% identical at the amino acid level to human acid beta-galactosidase. A homozygous recessive mutation, 200G-A (R60H), was found to cause canine GM1-gangliosidosis. The mutation created a new restriction enzyme site for Pml1.
Fan et al. (1999) proposed a molecular therapeutic strategy for Fabry disease (301500) in which competitive inhibitors are administered as 'chemical chaperones' at subinhibitory intracellular concentrations. Using a similar approach, Matsuda et al. (2003) synthesized a galactose derivative, N-octyl-4-epi-valienamine (NOEV), for a molecular therapy of beta-galactosidosis. They showed that NOEV is a potent inhibitor of lysosomal beta-galactosidase in vitro. Addition of the inhibitor in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOEV to a mouse model of juvenile GM1-gangliosidosis, expressing the human R201C (611458.0003) mutant enzyme protein, resulted in significant enhancement of the enzyme activity in the brain and other tissues. Immunohistochemical stain revealed a decrease in the amount of GM1 and GA1 in neuronal cells in the frontotemporal cerebral cortex and brainstem. Matsuda et al. (2003) concluded that chemical chaperone therapy may be useful for certain patients with beta-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.
In the mouse brain, Sano et al. (2009) demonstrated that Glb1 is a normal constituent of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), which define the sites of ER/mitochondrial juxtaposition that control calcium influx between these organelles. Brains of Glb1-null mice showed GM1 accumulation in glycosphingolipid fractions of these membranes, and was associated with increased levels of phosphorylated Ip3r1 (ITPR1; 147265), a calcium channel. These findings were also associated with altered mitochondrial calcium homeostasis: increased calcium levels in mitochondria resulted in mitochondrial membrane permeabilization, opening of the permeability transition pore, and activation of the mitochondrial apoptotic pathway. These effects could be reversed with a calcium blocker. Sano et al. (2009) concluded that pathologic GM1 accumulation alters the normal crosstalk between ER and mitochondria, promoting the formation of a calcium-channel megapore that results in an ER stress response and a disruption in mitochondrial homeostasis, ultimately causing neuronal cell death. The findings also pointed to a role for GM1 in the regulation of calcium influx between the ER and mitochondria.
De Wit et al. (1977) and de Wit et al. (1979) concluded that a beta-galactosidase locus was on chromosome 22 (22q13-qter). This locus was designated beta-galactosidase-2 (GLB2), but subsequent studies showed that 'the second beta-galactosidase locus' codes for a lysosomal protective protein (CTSA; 613111) for both beta-galactosidase and neuraminidase and is situated on chromosome 20, not 22.
By study of mouse-man somatic hybrid cells, Rushton and Dawson (1977) concluded that all the glycosphingolipid beta-galactosidases are on chromosome 12, but the authors could not answer the question of the number of separate beta-galactosidases. However, de Wit et al. (1979) found no evidence of a GLB1 locus on chromosome 12.
In a case of de novo interstitial deletion of 3p14.2-p11, Hertz et al. (1988) found normal levels of beta-galactosidase-1, thus excluding this region as the site of the gene.
In a Japanese patient with the infantile form of GM1-gangliosidosis (GM1G1; 230500), Nishimoto et al. (1991) identified a 145C-T transition in the GLB1 gene, resulting in an arg49-to-cys (R49C) substitution. A putative second mutant allele was not identified. GLB1 mRNA was decreased, but detectable.
In a Japanese patient with the infantile form of GM1-gangliosidosis (GM1G1; 230500), Nishimoto et al. (1991) identified a homozygous 1369C-T transition in the GLB1 gene, resulting in an arg457-to-ter (R457X) substitution. GLB1 mRNA was undetectable.
In 4 Japanese patients with the juvenile form of GM1-gangliosidosis (GM1G2; 230600), Nishimoto et al. (1991) identified a 601C-T transition in exon 6 of the GLB1 gene, resulting in an arg201-to-cys (R201C) substitution. One patient was homozygous for the mutation; the second mutant allele could not be identified in the 3 remaining patients. All had detectable GLB1 mRNA.
Yoshida et al. (1991) identified a heterozygous R201C mutation in a Japanese patient with the late infantile form of GM1-gangliosidosis (see 230600). Yoshida et al. (1991) stated that the nucleotide change was 635C-T. A second mutant GLB1 allele was not identified. Beta-galactosidase activity was 3% of normal controls.
Caciotti et al. (2003) found that the R201C mutant enzyme had 12.9% residual activity, but that activity was decreased to 3.8% when combined with an in cis L436F polymorphism, indicating that the polymorphism could modulate enzyme activity.
In 6 Japanese patients with the adult/chronic form of GM1-gangliosidosis (GM1G3; 230650), Nishimoto et al. (1991) identified a 152T-C transition in the GLB1 gene, resulting in an ile51-to-thr (I51T) substitution.
Yoshida et al. (1991, 1992) found the I51T mutation in Japanese patients with adult GM1-gangliosidosis. The authors stated that the nucleotide change was 186T-C. All patients except 1 were homozygotes. One patient was a compound heterozygote with an R457Q mutation (611458.0008). Clinically, the compound heterozygous patient showed more severe neurologic manifestations and a more rapid clinical course than did the homozygotes. The I51T allele showed 5.28 to 7.28% residual enzyme activity, whereas the compound heterozygous patient had 4.24% residual activity. The mutations causing residual enzyme activity appeared to be related to severity of clinical manifestations, but other genetic or environmental factors likely also contributed to the phenotype since there was considerable variation in age of onset and clinical course among I51T homozygotes.
In 2 Japanese patients with the infantile form of GM1-gangliosidosis (GM1G1; 230500), Yoshida et al. (1991) found a 165-bp duplication (positions 1103-1267), producing an abnormally large mRNA. One patient was probably homozygous and the other heterozygous.
In a Japanese patient with the infantile form of GM1-gangliosidosis (GM1G1; 230500), Yoshida et al. (1991) found a 401G-A transition in the GLB1 gene, resulting in a gly123-to-arg (G123R) substitution. The patient had 0.65% residual enzyme activity. A second mutant allele was not identified.
In a Japanese patient with the infantile form of GM1-gangliosidosis (GM1G1; 230500), Yoshida et al. (1991) identified a 981A-G transition in the GLB1 gene, resulting in a tyr316-to-cys (Y316C) substitution. The patient had 0.69% residual enzyme activity. A second mutant allele was not identified. In the same patient, Oshima et al. (1992) identified the second mutant GLB1 allele, a 23-bp duplication in exon 3 (611458.0012).
In a Japanese patient with the adult/chronic form of GM1-gangliosidosis (GM1G3; 230650), Yoshida et al. (1991) identified compound heterozygosity for 2 mutations in the GLB1 gene: a 1404G-A transition resulting in an arg457-to-gln (R457Q) substitution, and I51T (611458.0004). Beta-galactosidase activity was 4.24% of normal controls in patient lymphoblasts.
In 3 affected individuals from 2 unrelated families with Morquio syndrome B (MPS4B; 253010), also known as mucopolysaccharidosis type IVB, Oshima et al. (1991) identified compound heterozygosity for 2 mutations in the GLB1 gene. All patients shared a heterozygous 851-852TG-CT change, resulting in a trp273-to-leu (W273L) substitution, and another pathogenic change (R482H, 611458.0010 and W509C, 611458.0011, respectively). The W273L mutant showed 8% residual enzyme activity. The R482H mutant and W509C mutants had no residual enzyme activity.
Paschke et al. (2001) identified the W273L mutation in 14 of 15 Morquio syndrome B patients.
For discussion of the 1479G-A transition in the GLB1 gene, resulting in an arg482-to-his (R482H) substitution, that was found in compound heterozygous state in a patient with mucopolysaccharidosis syndrome IVB (MPS4B; 253010) by Oshima et al. (1991), see 611458.0009. transition in the GLB1 gene.
Studying several Italian patients with infantile GM1-gangliosidosis (GM1G1; 230500), Mosna et al. (1992) found 1 patient who was homozygous for the R482H substitution. The R482H mutation was found in the heterozygous state in 6 other unrelated patients with the severe form of GM1-gangliosidosis, but not in 100 normal chromosomes. Thus, depending on the allele with which it is paired, the R482H substitution can result in either severe or relatively mild disease.
Suzuki and Oshima (1993) likewise emphasized the occurrence of wide variation in the clinical phenotype observed with the R482H mutation depending on the nature of the second allele with which it is paired. It may lead to juvenile (230600) or chronic/adult (230650) GM1-gangliosidosis or intermediate types between infantile GM1-gangliosidosis and Morquio syndrome type B. They suggested the designation 'beta-galactosidosis' for this group of diseases with mutations of the GLB1 gene.
For discussion of the 1561G-T transversion in the GLB1 gene, resulting in a trp509-to-cys (W509C) substitution, that was found in compound heterozygous state in a patient with mucopolysaccharidosis type IVB by Oshima et al. (1991), see 611458.0009.
In a 5-year-old boy with the infantile form of GM1-gangliosidosis (GM1G1; 230500), Oshima et al. (1992) found compound heterozygosity for 2 mutations in the GLB1 gene: a 23-bp duplication in exon 3 and Y316C (611458.0007). The duplication resulted in a premature stop codon after translation of 36 amino acids. Homologous sequences in the area of duplication suggested that the mutation resulted from an unequal crossover. The boy had hepatomegaly and liver dysfunction at 6 months of age. Cherry-red spots were found bilaterally at the age of 1 year and the diagnosis of GM1-gangliosidosis was made. He deteriorated to a state of decerebrate rigidity by the age of 5 years. The patient had previously been reported by Yoshida et al. (1991).
In affected members of 2 presumably unrelated families of Scandinavian origin with adult GM1-gangliosidosis (GM1G3; 230650), Chakraborty et al. (1994) identified a heterozygous 245C-T transition in the GLB1 gene, resulting in a thr82-to-met (T82M) substitution. Nucleotide 245 is part of a split codon that straddles the intron between exons 2 and 3. Functional expression studies showed that the mutant protein had 3 to 4% residual enzyme activity. The 245C-T transition was inherited from the father in both families. In 1 family, the other allele showed a splice site mutation (611458.0014) with no residual activity. Thus, the T82M substitution resulted in enough functional enzyme to produce a mild adult form of the disease, even in the presence of a second mutation that probably produced a nonfunctional enzyme. Chakraborty et al. (1994) speculated that homozygosity for the T82M mutation might present in late life with symptoms resembling those of basal ganglia disease, such as Parkinson disease, since Goldman et al. (1981) showed that in the adult form of GM1-gangliosidosis, storage is focal and confined mainly to basal ganglia.
In 2 sibs affected by the severe infantile form of GM1-gangliosidosis (GM1G1; 230500), Morrone et al. (1994) identified homozygosity for a 1-bp insertion (insT) in the +3 position of intron 1 of the GLB1 gene immediately downstream of the conserved GT splice donor dinucleotide. The insertion resulted in 2 aberrant transcripts, 1 containing a 20-nucleotide insertion derived from the 5-prime end of intron 1 and a second in which sequences encoded by exon 2 were deleted during the splicing process.
Chakraborty et al. (1994) identified heterozygosity for the intron 1 insT mutation in 2 sibs with GM1-gangliosidosis. They were compound heterozygous for another GLB1 mutation that had residual enzyme activity, T82M (611458.0013), yielding a phenotype consistent with the adult form of the disorder (GM1G3; 230650).
In a 15-year-old Japanese boy who presented with progressive generalized skeletal dysplasia without neurologic manifestations (MPS4B; 253010), Ishii et al. (1995) found compound heterozygosity for 2 mutations in the GLB1 gene: a tyr83-to-his (Y83H) substitution and R482C (611458.0016). The R482C mutant was found to express no detectable enzyme activity, whereas the Y83H expressed a low enzyme activity (2 to 5% of normal).
For discussion of the arg482-to-cys (R482C) mutation in the GLB1 gene that was found in compound heterozygous state in a patient with mucopolysaccharidosis type IVB (MPS4B; 253010) by Ishii et al. (1995), see 611458.0015.
Boustany et al. (1993) reported that 2 of 6 patients of Puerto Rican origin with infantile GM1-gangliosidosis (GM1G1; 230500) were homozygous for a 622C-T transition in the GLB1 gene, resulting in an arg208-to-cys (R208C) substitution.
In a subsequent analysis, Chiu et al. (1996) found that 3 of 4 additional patients with infantile GM1-gangliosidosis were of Puerto Rican ancestry. Of these, 2 were homozygotes for the R208C mutation, and another patient, also Puerto Rican, was a heterozygote. The authors hypothesized that this mutation arose in Puerto Rico and subsequently moved to South and North America.
Hinek et al. (2000) reported a patient with Morquio syndrome B (MPS4B; 253010) who had a homozygous gly438-to-glu (G438E) substitution in the GLB1 gene. The substitution is located in the coding region common to the lysosomal enzyme and the S-Gal/EBP protein, resulting in disruption of this splice variant. Fibroblasts derived from this patient showed impaired tropoelastin secretion and lack of assembly into extracellular insoluble elastin. The results suggested that cellular deficiency of S-Gal underlies the connective tissue and skeletal deformations characteristic of Morquio syndrome B.
In a patient with infantile GM1-gangliosidosis and cardiac involvement (see 230500), Hinek et al. (2000) identified a mutation in the GLB1 gene, resulting in an arg351-to-ter (R351X) substitution. The mutant protein was associated with impaired elastogenesis due to destabilization of both beta-galactosidase and S-Gal mRNAs. Beta-galactosidase activity was less than 2% of control values. In addition to classic features of type I disease, the patient had cardiomegaly, congestive heart failure, left ventricular hypertrophy, and decreased contractility.
In a French patient with the Morquio syndrome B phenotype (MPS4B; 253010), Paschke et al. (2001) identified compound heterozygosity for 2 mutations in the GLB1 gene: a 1532A-C transversion resulting in a thr500-to-ala (T500A) substitution, and Q408P (611458.0021). The T500A mutation had been studied by Hinek et al. (2000).
In a patient with Morquio syndrome type B (MPS4B; 253010), Paschke et al. (2001) identified compound heterozygosity for 2 mutations in the GLB1 gene: a 1257A-G transition resulting in a gln408-to-pro (Q408P) substitution, and T500A (611458.0020).
In a child with the late-infantile form of GM1-gangliosidosis (GM1G2; 230600) with onset at age 17 months, Caciotti et al. (2003) found compound heterozygosity for 2 mutations in the GLB1 gene. One allele was a complex allele consisting of the R201C substitution (611458.0003) and a leu436-to-phe (L436F) polymorphism in cis inherited from the mother, and the other allele had a 202C-T transition resulting in an arg68-to-trp (R68W) substitution inherited from the father. Biochemical studies showed 1.4% residual enzyme activity in the patient's leukocytes. Further studies showed that the R68W change rendered GLB1 enzymatically inactive and the R201C mutant gave 12.9% residual activity. However, the R201C and L436F allele had only 3.8% residual activity, indicating that the polymorphism could modulate enzyme activity. The child developed blindness and spasticity at age 3 years and died of renal failure at age 6.5 years. The clinical and molecular characterization of the disorder in this patient as late-infantile GM1-gangliosidosis was in keeping with a clear-cut division between 2 forms of the type II phenotype. The L436F polymorphism was thought to modify the effect of the R201C mutation in the direction of greater severity.
In 2 sibs from northeast Italy with infantile GM1-gangliosidosis with cardiac involvement (see 230500), Morrone et al. (2000) identified a homozygous 176G-A transition in exon 2 of the GLB1 gene, resulting in an arg59-to-his (R59H) substitution within the region common to the lysosomal enzyme and the EPB. In addition to classic type I symptoms, the patients showed dilated cardiomyopathy and hypertrophic cardiomyopathy, respectively .
Santamaria et al. (2007) identified the R59H mutation in 6 (15.8%) of 38 mutant GLB1 alleles in patients with GM1-gangliosidosis from South America, mainly Argentina. All had the type I phenotype (GM1G1; 230500). Two unrelated patients of Gypsy origin were homozygous for this mutation. Some, but apparently not all, had cardiac involvement.
In an infant with type I GM1-gangliosidosis with cardiac involvement (see 230500), Morrone et al. (2000) identified a homozygous A-to-G transition in intron 14 of the GLB1 gene, resulting in a frameshift and premature termination. The splice site occurs in a region that is common to the lysosomal enzyme and the EPB. In addition to classic type I symptoms, the patient showed dilated cardiomyopathy and a hypertrophied left ventricle.
In an infant with type I GM1-gangliosidosis with cardiac involvement (see 230500), Morrone et al. (2000) identified a homozygous 1771T-A transversion in exon 16 of the GLB1 gene, resulting in a tyr591-to-asn (Y591N) substitution, in a region common to the lysosomal enzyme and the EPB. The child had dilated cardiomyopathy and aortic stenosis. An affected fetus had the same mutation. The family was from Campania in southern Italy.
In 2 male twins with type I GM1-gangliosidosis with cardiac involvement (see 230500), Morrone et al. (2000) identified a homozygous 1772A-G transition in exon 16 of the GLB1 gene, resulting in a tyr591-to-cys (Y591C) substitution in a region common to the lysosomal enzyme and the EPB. Both had right intraventricular conduction delay. The family was from Apulia in southern Italy.
In a patient (patient 1) with mucopolysaccharidosis type IVB (MPS4B; 253010), Caciotti et al. (2021) identified compound heterozygosity for 2 mutations in the GLB1 gene: a splicing mutation (c.75+2T-G) predicted to interrupt a canonical splice donor site, and a c.2030T-G transversion predicted to result in a val677-to-gly (V677G; 611458.0028) substitution in the C-terminal region. The mutations were identified by Sanger sequencing of the GLB1 gene. The V677G mutation was reported in 2 of 249,468 alleles in only heterozygous state in the gnomAD database. Western blot analysis in patient lymphocytes showed increased expression of both GLB1 and EBP proteins.
For discussion of the c.2030T-G transversion in the GLB1 gene, predicted to result in a val677-to-gly (V677G) substitution, that was found in compound heterozygous state in a patient with mucopolysaccharidosis type IVB (MPS4B; 253010) by Caciotti et al. (2021), see 611458.0027.
In a 5-year-old Emirati boy, born to consanguineous parents, with the infantile form of GM1-gangliosidosis (GM1G1; 230500), Mohamed et al. (2020) identified homozygosity for a c.451G-T transversion in exon 4 of the GLB1 gene, resulting in an asp151-to-tyr (D151Y) substitution at a conserved residue. The mutation was identified by Sanger sequencing of the GLB1 gene. Protein modeling predicted that the mutation affected overall protein secondary structure. Testing in patient fibroblasts showed less than 1% residual beta-galactosidase enzyme activity. Immunofluorescence staining in patient fibroblasts demonstrated that the mutant protein was improperly trafficked and processed, resulting in trapping in the ER. Further studies in patient fibroblasts demonstrated that ER trapping of the mutant protein did not trigger an unfolded protein response.
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