Other entities represented in this entry:
HGNC Approved Gene Symbol: HEXB
SNOMEDCT: 23849003; ICD10CM: E75.01;
Cytogenetic location: 5q13.3 Genomic coordinates (GRCh38) : 5:74,640,023-74,721,288 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q13.3 | Sandhoff disease, infantile, juvenile, and adult forms | 268800 | Autosomal recessive | 3 |
The HEXB gene encodes the beta subunit of the enzyme hexosaminidase (EC 3.2.1.52), which is involved in the breakdown of gangliosides. There are 2 isoenzymes of hexosaminidase: Hex-A, which is encoded by the HEXA gene (606869), and Hex-B. Beutler et al. (1975) concluded that Hex-A has the structure alpha-beta, whereas Hex-B has the structure beta-beta.
O'Dowd et al. (1985) cloned a human HEXB cDNA from an SV40-transformed fibroblast cDNA library. The cDNA encodes a deduced 556-amino acid protein.
Bapat et al. (1988) cloned the murine beta subunit of hexosaminidase. The cDNA corresponded to a polypeptide of 536 amino acids, which shows 75% homology with the human peptide.
Proia (1988) showed that the beta-chain coding region is divided into 14 exons distributed over about 40 kb of DNA. Comparison with the alpha-chain gene showed that 12 of the 13 introns interrupt the coding regions at homologous positions. This extensive sharing of intron placement demonstrates that the alpha and beta chains evolved by way of duplication of a common ancestor.
Neote et al. (1988) determined that the promoter region of the HEXB gene is GC-rich, with several GC boxes and a CAAT box.
Hechtman and Rowlands (1979) studied a temperature-sensitive mutant of hexosaminidase B. Mahuran et al. (1982) provided biochemical evidence that the beta(2) subunit may consist of 2 dissimilar polypeptide chains: beta(a)beta(b). Genetic data suggest that these are the product of a single locus.
Pennybacker et al. (1996) identified domains in human hexosaminidase that confer distinctive substrate specificity to Hex-A (composed of alpha-beta chains), Hex-B (beta-beta), and Hex-S (alpha-alpha) isozymes. The active site on the beta subunit primarily degrades neutral substrates while the alpha-subunit site is active against sulfated substrates. Only Hex-A, together with the GM2 activator protein, can degrade GM2 ganglioside. Pennybacker et al. (1996) generated chimeric hexosaminidase subunits by interchanging analogous regions of the alpha and beta subunits. Chimeric constructs were expressed in HeLa cells and selected constructs were produced in the baculovirus expression system to determine their ability to degrade GM2 ganglioside in the presence of GM2 activator protein. Their results allowed them to define 2 noncontiguous sequences in the alpha subunit (amino acids 1-191 and 403-529) which, when substituted into analogous positions in the beta subunit, conferred activity against the sulfated substrate. Pennybacker et al. (1996) also found that amino acids 225-556 in the beta subunit are required for activator-dependent GM2 ganglioside degradation by HEXA.
Alterations in chromosome 5q13 are a frequent finding in hairy cell leukemia (HCL). Hammarsund et al. (2004) reported that a 5q13.3 breakpoint discovered in an HCL patient disrupted a conserved alternative isoform of HEXB. This isoform directly overlapped, in a cis-antisense fashion, exon 1 of ENC1 (605173), and was thus named ENC1AS. Purified HCL tumor cells from 26 HCL patients showed striking upregulation of ENC1 in all 26 samples analyzed. Hammarsund et al. (2004) identified a complex 5-prime regulatory mechanism involving an inverse expression of the ENC1 and the ENC1AS transcripts in several tissues, suggesting that expression of ENC1AS may regulate ENC1 levels.
Using RNA interference to deplete host genes in Mycobacterium marinum (Mm)-infected Drosophila S2 cells, which share properties with mammalian macrophages, Koo et al. (2008) identified a mycobactericidal role for Hexb. They confirmed the importance of mammalian Hexb in controlling Mm growth using macrophages from Hexb -/- mice. Treatment of Hexb -/- mouse cells with Ifng (147570) abolished their susceptibility to Mm. Exposure of mouse macrophages to Mm, with or without phagocytosis, induced Hexb secretion, suggesting that Mm comes into contact with Hexb at the plasma membrane. Incubation of Mm with Hexb, at neutral or acidic pH, killed Mm. Koo et al. (2008) concluded that HEXB is a peptidoglycan hydrolase and proposed that it is involved in restricting mycobacteria growth even before the onset of adaptive immunity.
The HEXB locus has been assigned to chromosome 5 (Gilbert et al., 1975).
Various Sandhoff strains, even cells from the infantile and the rare juvenile forms, fail to complement in heterokaryons, suggesting that these are the result of allelic mutations in the beta subunit of HEXB. Dana and Wasmuth (1982) did cytogenetic and biochemical analyses of spontaneous segregants from Chinese hamster-human interspecific hybrid cells (which contained human chromosome 5 and expressed the 4 syntenic genes LEUS, HEXB, EMTB, and CHR), the hybrid cell being subjected to selective conditions requiring them to retain the LEUS gene. From these analyses, Dana and Wasmuth (1982) concluded that the order is as listed above and that the specific locations are: LEUS, 5pter-q1; HEXB, 5q13; EMTB, 5q23-q35; CHR, 5q35. In a child with a de novo balanced translocation t(5;13)(q11;p11), Mattei et al. (1984) found decreased levels of Hex-B, suggesting to these workers that the HEXB gene assignment can be narrowed to 5q11.
Killary et al. (1986) assigned the HEXB locus to mouse chromosome 13 by study of mouse-hamster hybrids.
O'Brien (1978) made suggestions for the nomenclature of alleles at the HEX alpha and beta loci. The alleles at the beta locus in his system are numbered as follows: 1--wildtype; 2--Sandhoff; 3--normal with deficient Hex-A and Hex-B.
Bikker et al. (1989) demonstrated a 16-kb deletion in 1 allele of the HEXB gene (606873.0001) in 2 apparently unrelated patients with Sandhoff disease (268800)
Oonk et al. (1979) reported the cases of 2 adult sisters with spinocerebellar degeneration and very low activities of both Hex-A and Hex-B. Bolhuis et al. (1987) concluded that the disorder was the result of a 'destabilizing mutation' in the HEXB locus. Bolhuis et al. (1993) demonstrated that these 2 sisters were compound heterozygotes for an mRNA-negative allele on 1 chromosome 5 and an R505Q mutation (606873.0009) on the homologous chromosome. Transfection of COS cells with a cDNA construct containing the R505Q mutation resulted in the expression of a labile form of beta-hexosaminidase, thus confirming their earlier conclusion.
Neufeld (1989) provided a review of the disorders related to mutations in the HEXA and HEXB genes. Mahuran (1998) stated that he maintains a database of published hexosaminidase and GM2A (613109) mutations and that the database contains 23 HEXB mutations, 86 HEXA (606869) mutations, and 4 GM2A mutations.
Among 12 unrelated Italian patients with Sandhoff disease, 11 of whom had the infantile type, Zampieri et al. (2009) identified 11 different mutations in the HEXB gene, including 6 novel mutations (see, e.g., 606873.0017 and 606873.0018). The common 16-kb deletion (606873.0001) was not identified in this patient cohort.
In 2 sibs with adult-type Sandhoff disease, Santoro et al. (2007) identified homozygosity for a missense mutation in the HEXB gene (D494G; 606873.0019). Leukocyte enzyme analysis showed reduced total Hex activity, absent Hex-B activity, and normal Hex-A activity. The mutation segregated with the disorder in the family.
By field inversion gel electrophoresis (FIGE) of SfiI-digested chromosomal DNA, Bikker et al. (1989) demonstrated a 16-kb deletion in 1 allele of the HEXB gene in 2 apparently unrelated patients with Sandhoff disease (268800). Mahuran (1994) pointed out that the 50-kb deletion (50-KB DEL) originally reported by Bikker et al. (1989) is the same as the 16-kb deletion described by Neote et al. (1990). The size was incorrectly estimated by Bikker et al. (1989); see Bolhuis and Bikker (1992). In conventional Southern blot analysis, this deletion was masked by hybridization of bands from the other allele. Among 14 patients with Sandhoff disease from different parts of Europe, Bikker et al. (1990) found homozygosity for the deletion in 2 and heterozygosity in 7. It appeared that the deletion started in intron 5, extending in the 5-prime direction and causing the loss of exons 1 to 5 and the promoter area of the HEXB gene.
In DNA from fibroblasts of a patient with the infantile form of Sandhoff disease, Neote et al. (1990) identified a deletion of approximately 16 kb, including the HEXB promoter, exons 1 through 5, and part of intron 5. The deletion probably arose from recombination between 2 Alu sequences, with the breakpoints occurring at the midpoint between the left and right arms in each case and regenerating an intact Alu element in the deletion sequence. The deletion allele accounted for 8 of 30 Sandhoff mutant alleles analyzed. It was present in homozygous state in 2 cell lines from patients with the infantile form, in heterozygous form together with an intron 12 deletion in a juvenile case, and in heterozygous form in 2 adult Sandhoff cases. The last 3 cases plus 1 infantile case had the Alu-type deletion in compound heterozygous (i.e., heteroallelic) state (see 606873.0014). McInnes et al. (1992) reported that this 16-kb deletion accounted for 27% of the Sandhoff alleles they analyzed. This null allele was associated with the juvenile pro417-to-leu mutation (606873.0007) which interfered with the normal acceptor splice site. This combination in a French Canadian family was accompanied by a very mild phenotype which McInnes et al. (1992) attributed to differences in racial background.
In a case of the juvenile form of Sandhoff disease (268800) reported by Wood and MacDougall (1976), Nakano and Suzuki (1989) showed that a cDNA clone isolated from fibroblasts contained an extra 24-base segment between exons 12 and 13. This segment was identified as the 3-prime terminus of intron 12. The remainder of the coding sequence was completely normal. The insertion was 'in frame' and added 8 amino acids between amino acids 491 and 492 of the enzyme protein. It was located only 5 amino acids away from a possible glycosylation site. Gene amplification by the PCR and subsequent sequencing of genomic DNA showed that the patient was a compound heterozygote. In 1 allele there was a single nucleotide transition from normal G to A at 26 bases from the 3-prime terminus of intron 12. This mutation generated a consensus sequence for the 3-prime splice site for an intron and thus explained the abnormal mRNAs that retain 24 bases of the 3-prime terminus of intron 12. The intron 12 and flanking exons 12 and 13 sequences were normal in the other allele. The other mutant allele was thought to be of an mRNA-negative type. The same mutation was found in a 35-year-old Japanese man with manifestations of juvenile Sandhoff disease: progressive neurogenic muscular atrophy, cerebellar ataxia, and mental deterioration beginning at age 10. Dlott et al. (1990) found the same mutation in cells from 2 juvenile Sandhoff disease patients and a third, asymptomatic individual.
Dreyfus et al. (1977) characterized a hexosaminidase variant that may represent unstable beta subunits. Dlott et al. (1990) demonstrated that this so-called 'hexosaminidase Paris' had an abnormally elongated beta subunit due to duplication of a region straddling the junction of intron 13 and exon 14, which generated an alternate splice site and caused an in-frame insertion of 18 nucleotides into the mRNA. The normal splice site seemed to be used to some extent, accounting for the residual Hex-A isoenzyme activity.
The ile207-to-val substitution was found to be a common polymorphism by Zhang et al. (1995) and Redonnet-Vernhet et al. (1996).
In a female patient with juvenile onset of Sandhoff disease (268800) manifest as a motor neuron disease (Cashman et al., 1986), Banerjee et al. (1991) found a heterozygous 1367A-C transversion in the HEXB gene, resulting in a tyr456-to-ser (Y456S) substitution derived from the maternal allele. The patient was also heterozygous for 2 polymorphisms: a 619A-G transition resulting in an ile207-to-val (I207V) substitution from the paternal allele, and K121R (606873.0008). The patient had progressive motor neuron disease that began at age 7 and was characterized by dysarthria, muscle wasting, fasciculations, and pyramidal tract dysfunction. Rectal biopsy at age 24 showed membranous cytoplasmic bodies in submucosal ganglion cells. Biochemical studies showed partial HexA (30-50% of controls) with absence of HexB. The unaffected mother also had partial HexA and partial HexB deficiency. In vitro functional expression studies by Banerjee et al. (1994) showed that the Y456S variant was completely nonfunctional and was predicted to interfere with formation of a functional dimer. Banerjee et al. (1994) proposed that the variant I207V beta-chain inherited from the father must undergo preferential association with the normal alpha-chains in the patient, thus producing only HexA. Further studies indicated that the I207V beta-chain does not self-associate at low concentrations. Thus, in a patient with a nonfunctional HEXB allele, the effective concentration of beta-chains is reduced to 50% of normal, and the remaining I207V chains fail to self-associate to form HexB, but can still dimerize with the abundant normal alpha-chains, thus producing partial beta-Hex A and no beta-Hex B.
Wakamatsu et al. (1992) studied a 39-year-old Japanese male with a mild clinical presentation of mental retardation and 'local panatrophy.' The parents were first cousins. HEXB activity was undetectable in the patient's leukocytes and fibroblasts and HEXA activity was decreased to 6 and 8% of control values, respectively. Rectal biopsy demonstrated membranous cytoplasmic bodies in neurons of Meissner plexus. The urine contained large amounts of neutral oligosaccharides. Wakamatsu et al. (1992) discovered a novel exon mutation affecting 3-prime splice site selection. Nucleotide sequence analysis of the HEXB gene showed 2 single base substitutions, one in exon 2 (A to G, a known polymorphism) and the other in exon 11 (C to T). Analysis of the beta-subunit mRNA demonstrated activation of a cryptic splice site in exon 11 as well as skipping of the exon. A transfection assay using a chimeric gene containing intron 10 flanked by cDNA sequences carrying the mutation confirmed that the single base substitution located at position 8 of exon 11 inhibited the selection of the normal 3-prime splice site. The CCG-to-CTG mutation resulted in substitution of leucine for proline-417 in exon 11. The mutation was present in homozygous state in the patient and in heterozygous state in the parents and a sister. Its effect was to abolish an MspI site.
McInnes et al. (1992) described a 57-year-old man with very mild manifestations of Sandhoff disease (268800) although his genotype and low residual enzyme activity were considered predictive of the much more severe juvenile Sandhoff disease. They demonstrated that the patient was a genetic compound of the infantile 5-prime deletion mutation described by Neote et al. (1990), a null mutation (606873.0001), and the juvenile intron 10/exon 11 C-to-T mutation. Of his 6 clinically unaffected sibs, 4 of them, ranging in age from 51 to 62 years, were also genetic compounds for the same 2 Sandhoff alleles. The variable phenotype associated with the intron 10/exon 11 C-to-T transition indicates that other unidentified factors determine the pathologic outcome of the mutation. Genetic variations in the RNA splicing machinery may be the explanation. The patient, a French Canadian, had had severe watery diarrhea over a 9-year period with intermittent moderate and diffuse abdominal pain, a 17-kg weight loss over a 7-year period, and increasing weakness. Physical examination showed lower limb hyperreflexia and impaired thermal sensitivity of legs and arms. Intolerance to warm weather due to impaired sweating, impaired sexual function progressing to complete impotence, mild urinary incontinence, and orthostatic hypotension were noted. One of the sisters, aged 58, had complained of diarrhea for 10 years and postural dizziness for 5 years.
In the course of studying a case of juvenile Sandhoff disease (268800), Wakamatsu et al. (1992) found the AAA-to-AGA polymorphism in exon 2, which results in alternative substitution of arginine for lysine-121.
In 2 sisters with adult Sandhoff disease (268800) presenting as spinocerebellar degeneration, reported by Oonk et al. (1979) and previously studied by Bolhuis et al. (1987), Bolhuis et al. (1993) found that the HEXB gene contained a G-to-A transition at nucleotide position 1514, resulting in a change in the electric charge at amino acid position 505 by substitution of glutamine for arginine in a highly conserved part of the beta chain. The nucleotide transition generated a new restriction site for DdeI, which was present in only 1 of the alleles. Bolhuis et al. (1993) demonstrated that the second allele was of mRNA-negative type. Thus, the patient was a genetic compound.
In a 35-year-old man who was evaluated at age 30 years because of slowly progressive lower limb weakness and diffuse fasciculations, Gomez-Lira et al. (1995) found compound heterozygosity with a common deletion at the 5-prime end of the HEXB gene and a C-to-T transition at nucleotide 1214, resulting in a pro405-to-leu amino acid substitution in the gene product. The patient was an executive secretary and had been a rock climber until age 29 years, when lower limb weakness began. On neurologic examination, moderate reduction in strength, widespread spontaneous fasciculations, and hyperactive deep tendon reflexes were observed. Intelligence was normal. The 5-prime deletion, which accounts for about 30% of the alleles causing Sandhoff disease, results in the infantile form of the disorder when present in homozygous state. The pro405-to-leu mutation was observed in homozygous state in a juvenile onset form of Sandhoff disease in a Japanese patient by Wakamatsu et al. (1992). The same mutation in compound heterozygosity with the 5-prime deletion was observed in an adult French Canadian patient by McInnes et al. (1992).
Genotyping individuals for Tay-Sachs disease (TSD) (272800) is based mainly on the heat lability of beta-hexosaminidase (Hex) A (606869) and the heat stability of Hex B. Mutations in the HEXB gene encoding the beta subunits of Hex that result in heat-labile hexosaminidase B thus may lead to erroneous enzymatic genotyping regarding TSD. Using single strand conformation polymorphism (SSCP) analysis for all 14 exons of HEXB followed by direct sequencing of aberrant fragments, Narkis et al. (1997) screened individuals whose Hex B was heat labile. These were Jewish and Arab individuals that had been identified by Navon and Adam (1990) and by Navon et al. (1985). The heat-labile mutation in these instances was identified as 1627 G-A. This caused an ala543-to-thr substitution in the beta-subunit protein. One individual with heat-labile Hex B was negative for the 1627 G-A mutation, as well as for the heat-labile mutation 1514 G-A (606873.0009), proving that there exists at least one other heat-labile Hex B mutation.
Zhang et al. (1995) found homozygosity for the ile207-to-val variant (606873.0005) in the unaffected mother of a child with the infantile form of Sandhoff disease (268800). The child was compound heterozygous for a large, partial deletion of the HEXB gene and for an allele with a C-to-T substitution at nucleotide 185, which replaced ser62 with leu. The deletion originated in intron 6, approximately 2.5 kb from the beginning of exon 7, and appeared to extend approximately 25 kb beyond the 5-prime end of the gene. Zhang et al. (1995) stated that this was the second largest deletion, after the very common 16-kb deletion (606873.0001), to be reported. The 16-kb deletion, spanning the promoter, exons 1-5, and part of intron 5 of the HEXB gene, is the most common defect, accounting for 27% of Sandhoff alleles examined.
See 606873.0012 and Zhang et al. (1995).
Rubin et al. (1988) described 2 sisters of French Canadian ancestry with a chronic Sandhoff phenotype (268800). Neote et al. (1990) demonstrated that these patients were heterozygous for the common 16-kb deletion of the 5-prime portion of the HEXB gene, (606873.0001). Such alleles do not transcribe HEXB mRNA. Hou et al. (1998) characterized the second mutant allele in these patients, a missense mutation in exon 13 of the HEXB gene that resulted in a pro504-to-ser amino acid substitution. This mutation produced a novel biochemical phenotype that impacted directly on the ability of HEXA to hydrolyze GM2. This was the first report of a mutation in the beta-subunit that affected the ability of HEXA to hydrolyze its natural, but not its artificial, substrates and that localized essential elements of the beta-chain from natural substrate hydrolysis to its C terminus.
Furihata et al. (1999) determined the molecular basis of infantile Sandhoff disease (268800) in a Greek Cypriot patient. The proband had died at the age of 3 years and his parents were not available for study; the molecular analysis was performed on the mother's first cousin who was a carrier. A G-to-C transversion was identified in 1 allele of her HEXB gene at position 5 of the 5-prime splice site of intron 8. A cDNA clone derived from lymphocyte HEXB mRNA lacked the last 4 nucleotides, GTTG, of exon 8, which created a premature termination 11 codons downstream. In vivo transcription of the mutant HEXB gene in CHO cells showed deletion of the GTTG.
Hara et al. (1994) found a 1-bp deletion, 76delA, in the HEXB gene in a patient from the Maronite community in Cyprus. Drousiotou et al. (2000) measured beta-hexosaminidases A and B in both leukocytes and serum in individuals from Cyprus and identified 35 carriers of Sandhoff disease (268800) among 244 random Maronite samples and 15 among 28 Maronites with a family history of Sandhoff disease, but only 1 carrier out of 115 random samples from the Greek community. Of the 50 Maronite carriers examined, 42 were found to have deletion of 76A.
In 2 unrelated Italian patients with infantile Sandhoff disease (268800), Zampieri et al. (2009) identified a homozygous 850C-T transition in the HEXB gene, resulting in an arg284-to-ter (R284X) substitution. Although the mutation was present in 29% of the alleles from 12 unrelated Italian patients with infantile Sandhoff disease, haplotype analysis did not indicate a founder effect. The mutation occurred in a CpG dinucleotide.
In 2 Italian sibs with infantile Sandhoff disease (268800), Zampieri et al. (2009) identified a homozygous 1-bp deletion (965delT) in the HEXB gene, predicted to result in a frameshift and premature termination. In vitro functional expression studies showed that the deletion resulted in nonsense-mediated mRNA decay.
In 2 sibs with adult-onset Sandhoff disease (268800), Santoro et al. (2007) identified a homozygous c.1556A-G transition (c.1556A-G, NM_00521) in the HEXB gene, resulting in an asp494-to-gly (D494G) substitution at a conserved residue. The substitution led to reduced Hex and absent Hex-B enzymatic activity, possibly via disruption of beta-beta homodimer assembly. The c.1556A-G transition also disrupted an exon splicing enhancer motif in exon 12; RT-PCR studies revealed partial aberrant splicing of exon 12, resulting in a frameshift and premature termination downstream of exon 11 and leading to partial haploinsufficiency in addition to the homodimer assembly defect. The mutation segregated with the disorder in the family.
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