Alternative titles; symbols
HGNC Approved Gene Symbol: IDUA
SNOMEDCT: 254069004, 26745009, 65327002, 73123008; ICD10CM: E76.01, E76.02, E76.03;
Cytogenetic location: 4p16.3 Genomic coordinates (GRCh38): 4:986,997-1,008,351 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.3 | Mucopolysaccharidosis Ih | 607014 | Autosomal recessive | 3 |
| Mucopolysaccharidosis Ih/s | 607015 | Autosomal recessive | 3 | |
| Mucopolysaccharidosis Is | 607016 | Autosomal recessive | 3 |
Alpha-L-iduronidase (IDUA; EC 3.2.1.76), the enzyme deficient in MPS I (see 607014, 607015, and 607016), hydrolyzes the terminal alpha-L-iduronic acid residues of the glycosaminoglycans dermatan sulfate and of heparan sulfate (Neufeld and Muenzer, 2001). It was originally defined as the 'Hurler corrective factor' (Barton and Neufeld, 1971).
Scott et al. (1990) used amino acid sequence data from purified human liver IDUA (Clements et al., 1989) to isolate both a genomic clone and a cDNA clone for IDUA. Scott et al. (1991) isolated and sequenced cDNA clones containing part of the human IDUA coding region and used PCR from reverse-transcribed RNA to obtain the full IDUA sequence. Analysis of the predicted 653-amino acid precursor protein showed that IDUA has a 26-amino acid signal peptide that is cleaved immediately before the amino terminus of the 74-kD polypeptide present in human liver IDUA. The protein sequence contains 6 potential N-glycosylation sites. Evidence of alternatively spliced mRNA from the IDUA gene was found in fibroblasts, liver, kidney, and placental RNA.
Scott et al. (1992) demonstrated that the IDUA gene spans approximately 19 kb and contains 14 exons. The first 2 exons are separated by an intron of 566 bp; a large intron of approximately 13 kb follows, and the last 12 exons are clustered within 4.5 kb.
By in situ hybridization and Southern blot analysis of mouse-human cell hybrids, Scott et al. (1990) determined that the IDUA gene maps to 4p16.3, not to chromosome 22 as earlier reported by Schuchman et al. (1982, 1984). Scott et al. (1990) confirmed the presence of human IDUA activity in human-mouse cell hybrids by using a monoclonal antibody specific to human IDUA. Scott et al. (1992) found that the polymorphic locus D4S111 used in the diagnosis of Huntington disease (143100) is the consequence of an 86-bp variable number tandem repeat (VNTR) within the IDUA gene. The gene mapped to chromosome 22 by Schuchman et al. (1982, 1984) by use of a polyclonal antibody in human-mouse cell hybrids may have been a crossreacting protein.
Grosson et al. (1994) mapped the homologous locus in the mouse, Idua, to chromosome 5 in a continuous linkage group that included the homolog of the Huntington disease gene.
Scott et al. (1990) failed to detect major deletions or gene rearrangements in the IDUA gene in any of the 40 MPS I patients studied by Southern blot analysis.
Scott et al. (1992) reported the presence of a common mutation accounting for 31% of MPS I alleles in a study of 64 MPS I patients. Chemical cleavage and then direct PCR sequencing detected the mutation. The mutation is a single base substitution that introduces a stop codon at position 402 (W402X; 252800.0001) of the alpha-L-iduronidase protein and is associated with an extremely severe clinical phenotype in homozygotes. Patients who are compound heterozygotes having one allele carrying the W401X mutation have a wide range of clinical phenotypes.
Scott et al. (1992) identified 2 additional mutations, one that introduces a stop codon at position 70 (Q70X; 252800.0002) and the other that alters the proline at position 533 to an arginine (P533R; 252800.0003) in the 653 amino acid alpha-L-iduronidase protein. Allele-specific oligonucleotides were used to detect the mutations in a group of 73 MPS I patients and Q70X was found to account for 15% of all MPS I alleles and P533R for 3% of MPS I alleles. Both mutations are associated with an extremely severe clinical phenotype in homozygotes. MPS I patients heterozygous for either mutation may have a wide range of clinical phenotypes. Mutations W402X (Scott et al., 1992), Q70X, and P533R accounted for 53% of MPS I alleles, which together define 28% of MPS I genotypes.
Bunge et al. (1995) identified 13 novel and 7 previously reported mutations of the IDUA gene, covering 88% of mutant alleles and 86% of genotypes, in a total of 29 patients with MPS I of differing clinical severity.
Scott et al. (1995) stated that 46 disease-producing mutations and 30 polymorphisms had been identified in the IDUA gene. In a mutation analysis of 85 mucopolysaccharidosis families (73 Hurler, 5 Hurler/Scheie, 7 Scheie), Beesley et al. (2001) identified 165 of the 170 mutant alleles. The 85 MPS I families were screened for 9 known mutations. W402X was the most frequent mutation in their population (43.3%) and Q70X was the second most frequent (15.9%). In 30 families, either one or both of the mutations were not identified, which accounted for 25.9% of the total alleles. All 14 exons of the alpha-L-iduronidase gene were then screened in those patients and 23 different sequence changes were found, 17 of which were previously unknown. The novel sequence changes included 4 deletions, 6 missense mutations, a splice site mutation, and a rare polymorphism.
Alleles that cause the milder phenotypes, Hurler/Scheie and Scheie syndromes, are often missense mutations. Tieu et al. (1995) reported 4 novel mutations of the IDUA gene in 1 patient with the Scheie syndrome and in 3 patients with the Hurler/Scheie syndrome. The novel mutations, all single base changes, encoded the substitutions R492P (252800.0011) (Scheie) and X654G (252800.0013), P496L, and L490P (252800.0012) (Hurler/Scheie). The L490P mutation was apparently homozygous, whereas each of the others was found in compound heterozygosity with a Hurler mutation. The deleterious nature of the mutations was confirmed by absence of enzyme activity upon transfection of the corresponding mutagenized cDNAs into COS-1 cells.
Aronovich et al. (1996) described the molecular defect underlying IDUA pseudodeficiency. The study was prompted by a patient who appeared to have, by biochemical study, both MPS I and MPS II. The common IDS mutation R468W (309900.0012) was found in the proband, his mother, and his sister, confirming transmission of Hunter syndrome. Additionally, the proband, his sister, and his father were found to be heterozygous for a common IDUA mutation, W402X (252800.0001). Notably, a new IDUA mutation, A300T (252800.0016), was identified in the proband, his sister, and his mother, accounting for reduced IDUA activity in these individuals. The proband's sister was asymptomatic and her cells demonstrated normal glycosaminoglycan metabolism, thus demonstrating that the W402X/A300T compound heterozygous genotype is an IDUA pseudodeficiency state.
Bunge et al. (1994) screened 46 European patients with mucopolysaccharidosis type I for mutations in the IDUA gene. The 2 common nonsense mutations, W402X and Q70X, were identified in 37% and 35% of mutant alleles, respectively. Considerable differences were seen in the frequency of these 2 mutations in patients from northern Europe (Norway and Finland) and other European countries (mainly the Netherlands and Germany). In Scandinavia, W402X and Q70X accounted for 17% and 62% of the MPS I alleles, respectively, whereas in other European countries W402X was about 2.5 times more frequent (48%) than Q70X (19%).
Gatti et al. (1997) screened 27 Italian MPS I patients for IDUA mutations. Mutations were found in 18 patients, with 28 alleles identified. The 2 common mutations in northern Europeans (W402X and Q70X) accounted for only 11% and 13% of the alleles, respectively. The R89Q (252800.0015) mutation, uncommon in Europeans, was found in 1 patient, accounting for 1 of 54 alleles (1.9%). The P533R, A327P and G51D mutations accounted for 11%, 5.6%, and 9.3% of the total alleles, respectively. The P533R mutation was relatively frequent in Sicily.
In a study of Israeli-Arab MPS I patients, Bach et al. (1993) identified 4 alleles, none of which had been found in Europeans. In all instances, the probands were homozygous and the parents heterozygous for the mutant alleles, as anticipated from the consanguinity in each family. One allele had 2 amino acid substitutions and was identified in a family from Gaza. The 3 single-substitution alleles were found in 7 families, 5 of them Druze, residing in a very small area of northern Israel, suggesting a founder effect.
Yamagishi et al. (1996) studied mutations in the IDUA gene from 19 Japanese MPS I patients, including 2 pairs of sibs, with various clinical phenotypes (Hurler, 6 cases; Hurler/Scheie, 7 cases; Scheie, 6 cases). Two common mutations accounted for 42% of the 38 alleles in their patients: a novel 5-bp insertion (704ins5; 252800.0014), which had not been found other populations, accounted for 18%, and an R89Q mutation, found uncommonly in Caucasians, accounted for 24%. None of the patients carried W402X or the Q79X mutations commonly found in Caucasians. Homozygosity for the 704ins5 mutation was associated with a severe phenotype, and the R89Q mutation was associated with a mild phenotype. Compound heterozygosity for these 2 mutations produced an intermediate phenotype. Haplotype analysis using polymorphisms linked to the IDUA locus demonstrated that each mutation occurs on a different specific haplotype, suggesting that individuals with each of these common mutations derive from common founders. The data documented the molecular heterogeneity and racial differences in mutations in MPS I.
Li et al. (2002) screened 22 unrelated MPS I patients from the United States and identified 11 different mutations in the IDUA gene, including 4 novel ones. The Q70X mutation (252800.0002) was found in 30% of alleles and the W402X mutation (252800.0001) was identified in 39% of alleles.
Lee et al. (2004) performed mutation analysis of the IDUA gene in 10 unrelated Korean patients with the various clinical phenotypes of MPS I and identified 7 different mutations, 4 of which were novel. The 704ins5 mutation (252800.0014) was found in 4 patients and the L346R mutation (252800.0020) in 6. These 2 mutations accounted for half the mutations found in Korean MPS I patients.
Clarke et al. (2019) reported an analysis of genotype-phenotype associations in 538 patients with mucopolysaccharidosis type I and biallelic mutations in the IDUA gene. Patients included 380 with a severe phenotype (Hurler syndrome, 607014) and 158 with an attenuated phenotype (Hurler-Scheie syndrome, 607015 or Scheie syndrome, 607016). The majority of the patients were ascertained from clinics in Europe or North America, and Latin America was reported to be underrepresented. Of the 1,076 alleles, 148 individual mutations were reported. Seventy-four mutations, which represented 50% of all mutations, appeared only once. About 67.6% of patients with a severe phenotype had genotypes in which both mutations were predicted to severely disrupt IDUA function: nonsense mutations were the most common (71.4%), followed by missense (17.8%), splice site (4.9%), and frameshift (2.6%). The most common genotypes in patients with a severe phenotype were homozygosity for W402X (252800.0001) (28.7%), compound heterozygosity for W402X and Q70X (252800.0002) (16.1%), and homozygosity for Q70X (6.3%). Of patients with an attenuated phenotype, 96.1% had at least 1 missense mutation or 1 intronic mutation. The most common mutations among patients with an attenuated phenotype were missense (71.8%), followed by nonsense (20.6%), small deletions with no frameshift (3.2%), and splice site (2.8%); the most common genotypes were homozygosity for L490P (252800.0012) (13.3%), homozygosity for P533R (252800.0003) (10.8%), and compound heterozygosity for L238Q and W402X (3.8%). Clarke et al. (2019) also reported several mutations where, even within the same genotype, the phenotype was variable. For example, homozygosity for an A327P mutation was reported in 5 patients, 3 of whom had severe disease and 2 of whom had attenuated disease. Homozygosity for a P533R mutation was reported in 24 patients, 7 of whom had severe disease and 17 of whom had attenuated disease.
Stoltzfus et al. (1992) cloned and characterized cDNA encoding the canine alpha-L-iduronidase and demonstrated mRNA deficiency in the MPS I dog. Menon et al. (1992) demonstrated that the canine IDUA gene has 14 exons spread over 13 kb. An unusual GC dinucleotide was found at the donor splice site of intron 11. A transcriptional start site was identified by primer extension 177 bp upstream of the initiator AUG codon. The upstream region was found to be similar to the promoter region of many housekeeping genes: it is GC rich and has 7 potential Sp1 binding sites but no TATA box or CAAT motif. The mutation in canine MPS I was found to be a G-to-A transition in the donor splice site in intron 1. The mutation caused retention of intron 1 in the RNA and created a premature termination codon at the exon-intron junction.
Scott et al. (1992) found that 31% of MPS I alleles in a study of 64 patients with Hurler syndrome (607014) had a trp402-to-ter (W402X) substitution in the alpha-L-iduronidase protein associated with very severe clinical phenotype in homozygotes. A G-to-A transition at nucleotide 1293 altered the W402 codon (TGG) to a stop codon (TAG); translation was terminated approximately two-thirds of the way through the 653-amino acid IDUA protein. The mutation was originally detected by chemical cleavage and then by direct PCR sequencing. The patients who were compound heterozygotes for the allele had a wide range of clinical phenotypes. Based on polymorphisms within the IDUA gene, Scott et al. (1992) determined that the W402X mutation is associated with 3 different haplotypes, implying more than one origin for the mutation or intragenic recombination. The mutation introduced a MaeI restriction endonuclease site into the gene, thus enabling simple detection of the mutation. Assessment of the efficacy of bone marrow transplantation in patients homozygous for the mutation is thus possible.
Significantly, the index case of Scheie syndrome (GM1323) reported by McKusick et al. (1965), who had been assumed to be a homozygote for a separate allele at the IDUA locus, was found in fact to be a compound heterozygote for the W402X allele. Biochemically, following the use of 2 different IDUA monoclonal antibodies, GM1323 fibroblasts had no detectable IDUA protein. They had approximately 0.3% of IDUA activity. This IDUA activity must result from a mild mutation in the other MPS I allele present in the patient. Subsequently, with definition of the mutation in the other allele (252800.0004), this proved to be the case.
Beesley et al. (2001) found that W402X accounted for 45.3% of mutant alleles in their study.
By chemical cleavage followed by direct PCR sequencing, Scott et al. (1992) detected and characterized a nonsense mutation, a C-to-T transition at nucleotide 296, that altered a gln codon at position 70 (CAG) to a stop codon (TAG). The termination of translation occurred soon after the mature 74-kD amino terminus of the IDUA protein. Using allele-specific oligonucleotides to detect mutations in a group of 73 MPS I patients, the authors found that the Q70X mutation accounted for 15% of all MPS I alleles. The mutation was associated with an extremely severe clinical phenotype in homozygotes. Patients who were compound heterozygotes showed a wide range of clinical phenotypes.
Beesley et al. (2001) found that Q70X accounted for 15.9% of alleles in their large study.
By chemical cleavage analysis followed by direct PCR sequencing, Scott et al. (1992) detected an alteration of the proline at position 533 to an arginine in the alpha-L-iduronidase protein. Using allele-specific oligonucleotides to screen for the mutation in a group of 73 MPS I (607014) patients, they found that the P533R mutation accounted for 3% of alleles. Homozygotes for the P533R mutation showed an extremely severe clinical phenotype; compound heterozygotes showed a wide range of clinical phenotypes. Scott et al. (1992) found that 3 mutations, W402X, Q70X, and P533R, were responsible for 53% of MPS I alleles, which together defined 28% of MPS I genotypes.
Using fluorescence-assisted mismatch analysis (FAMA) and cycle sequencing of the PCR products, Alif et al. (1999) screened for mutations in the IDUA gene in a group of 13 Moroccan patients with MPS I and their families, including 3 sibs and twin sibs. The P553R mutation, which is rare in Europeans, was identified in 92% of mutant alleles (24 of 26). This was said to be the highest frequency of this mutation detected in patients with Hurler syndrome. None of the patients carried the W402X (252800.0001) or the Q70X (252800.0002) allele, the most common MPS I mutations in Europeans.
In the fibroblast strain GM01323 derived from the index case of the Scheie syndrome (607016) reported by McKusick et al. (1965) and in a second cell line, GM01256, Moskowitz et al. (1993) found compound heterozygosity for the same 2 mutations: a G-to-A transition in intron 5, in position -7 from exon 6, and a W402X change (TGG to TAG) in exon 9. The latter mutation, trp402-to-ter (252800.0001), had previously been identified as a common MPS I mutation in the Caucasian population, present in homozygosity in some Hurler patients and in compound heterozygosity in patients with any form of MPS I, including the Scheie patient GM01323 (Scott et al., 1992). Moskowitz et al. (1993) proposed that the intron 5 mutation was responsible for the Scheie phenotype in these 2 patients. The mutation created a new acceptor splice site, causing 5 intronic nucleotides to be inserted into mRNA; this out-of-frame insertion led to an almost immediate termination codon. Additional splicing of transcripts of one or both alleles at some upstream cryptic site(s) was found. Since the normal splice site was not obliterated by the intron 5 mutation, its use would allow the synthesis of some completely normal enzyme. An analogous situation had been encountered in the HEXB gene (268800); mutations that create a new splice site without destroying the old one, thereby permitting expression of some functional beta-hexosaminidase, had been found in a patient with juvenile Sandhoff disease (Nakano and Suzuki, 1989) and in an individual with the asymptomatic 'hexosaminidase Paris' (Dlott et al., 1990) phenotype. Indeed, Ashton et al. (1992) and Scott et al. (1992) found a low level of immunoprecipitable alpha-L-iduronidase activity with normal K(m) and with probably normal specific activity in the Scheie fibroblast cell line GM01323. Although McKusick et al. (1972) suggested that the Scheie syndrome may represent homozygosity for a mild disease allele, based on the paradigm of hemoglobinopathies SS, CC and SC, molecular studies in lysosomal storage diseases, especially the GM2 gangliosidoses (272800) and Gaucher disease (230800), demonstrate the presence of multiple mutant alleles at each disease locus and the occurrence of compound heterozygosity as well as homozygosity in the milder phenotypes. The findings demonstrate that just one allele, if it permits residual enzyme activity, can protect from severe disease (Neufeld, 1991). Scheie syndrome must be genetically heterogeneous inasmuch as 2 other patients with this phenotype did not have the intron 5 allele. One wonders what the homozygote for this IVS5AS mutation might show phenotypically; the abnormalities might be relatively mild and late in onset, if present at all. By chemical cleavage and direct PCR sequencing, Scott et al. (1993) also found the mutation, which they referred to as 678-7g-to-a, in association with W402X in the index case of McKusick et al. (1965). Scott et al. (1993) concluded that since the W402X allele in other combinations is associated with severe disease, the splice acceptor site mutation is likely to be responsible for the mild clinical phenotype because it allows a very small amount of normal mRNA to be produced.
In a patient with Hurler syndrome (607014) in a consanguineous Muslim Arab family in Gaza, Bach et al. (1993) observed homozygosity for an IDUA allele containing 2 amino acid substitutions: a G-to-C transversion in exon 9 converting codon 409 from GGG (gly) to CGG (arg), and an A-to-T transversion in the termination codon 654 (TGA), converting it to a cys (TGT) residue. The cDNA sequence predicted an extension of 38 amino acids before the next termination codon was reached. Both mutations were found in heterozygous form in the DNA of each parent. Expression of cDNA mutagenized at one or both positions showed that gly409-to-arg caused a reduction of less than half the alpha-L-iduronidase activity, whereas the ter-to-cys mutation reduced activity by 98% compared with expression of normal cDNA.
Schaap and Bach (1980) found 13 Arab patients with Hurler syndrome (607014) but only 1 Jewish patient in Israel where ascertainment of the disorder had been complete for 15 years. The mutation in the Jewish patient was the deletion/insertion mutation described by Moskowitz et al. (1993). The Arab patients came from 8 families, 5 of which were Druze and 3 Muslim. Unexpectedly, Bach et al. (1993) found homozygosity for 3 different mutations distributed in 7 families, 5 of them Druze: mutations in exon 2 (tyr64-to-ter), exon 7 (gln310-to-ter; 252800.0007), and exon 8 (thr366-to-pro; 252800.0008). Transfection of mutagenized cDNA into COS-1 cells showed that the missense mutation thr366-to-pro permitted the expression of only trace amounts of alpha-L-iduronidase activity. The nonsense mutations were associated with abnormalities of RNA processing. The tyr64-to-ter mutation was accompanied by a very low level of mRNA and skipping of exon 2. Utilization of a cryptic splice site was observed with the gln310-to-ter mutation. The Druze and Muslim Arab populations have been separated by religion since the inception of the Ismalia or Druze religion in Egypt in the 11th century A.D. At present the Druze live in a defined geographic area of southern Syria, southern Lebanon, and northern Israel; they maintain an isolated social structure with a high rate of consanguineous marriages. The Druze population in Israel numbers about 60,000. Bach et al. (1993) anticipated that MPS in the Druze population would be caused by 1 founder mutation which might or might not be shared with the Muslim patients residing in the surrounding area. They were surprised to find that, in fact, there were 3 different mutations.
For discussion of the gln310-to-ter (Q310X) mutation in the IDUA gene that was found in homozygous state in patients with Hurler syndrome (607014) by Bach et al. (1993), see 252800.0006.
For discussion of the thr366-to-pro (T366P) mutation in the IDUA gene that was found in homozygous state in patients with Hurler syndrome (607014) by Bach et al. (1993), see 252800.0006.
In a patient with a severe form of Hurler syndrome (607014), Scott et al. (1993) found that the Q70X (252800.0002) mutation was combined with an allele carrying a deletion of a single G residue at cDNA base 1702, resulting in a frameshift.
Bunge et al. (1994) identified an R621X mutation due to a CGA-to-TGA transition in a patient with Hurler syndrome (607014). The patient was a compound heterozygote, the other allele being the common W402X mutation (252800.0001).
In a patient with Scheie syndrome (607016), Tieu et al. (1995) found a heterozygous G-to-C transversion in codon 492, corresponding to a change of arginine (CGG) to proline (CCG). The mutation, which created an ApaI site, was inherited from the patient's mother. No alpha-L-iduronidase activity was observed when cDNA containing the R492P mutation was expressed in COS-1 cells. Even though no activity was observed, this mutation must be presumed responsible for the mild Scheie phenotype, because the other allele carried the gln70-to-ter Hurler mutation associated with severe disease (252800.0002). This was the third mutation to be described in the Scheie syndrome; in each case, there was compound heterozygosity for a common Hurler mutation.
Tieu et al. (1995) demonstrated that the Hurler/Scheie (607015) cell line GM00512 had a T-to-C transition in codon 490, converting leucine (CTG) to proline (CCG), and creating a SmaI site. No alpha-L-iduronidase activity was detected when cDNA containing the L490P mutation was expressed in COS-1 cells. There was no evidence for heterozygosity either in the genomic sequence or in the restriction digest, suggesting that the mutation was present in homozygous form. However, hemizygosity, because of either deletion of the IDUA gene on 1 chromosome or uniparental disomy, had not been ruled out. The GM00512 cell line was derived from a patient of Asian Indian origin, whose parents were not known to be consanguineous. Homozygosity had been observed previously only in consanguineous families or for the most common mutations, W402X (252800.0001) and Q70X (252800.0002). It is therefore possible that the L490P mutation is relatively common among Indian MPS I patients.
In a patient with Hurler/Scheie syndrome (607015), Tieu et al. (1995) observed a heterozygous T-to-G transversion in the IDUA gene that changed the termination codon (TGA) to glycine (GGA), which predicted an extension of 38 amino acids at the C terminus of the protein. The mutation, which created a BstNI site, was inherited from the mother. A very low level of alpha-L-iduronidase activity was observed when the mutagenized cDNA was expressed in COS-1 cells. This mutation must have been responsible for the Hurler/Scheie phenotype, as the other allele carried the Q70X Hurler mutation (252800.0002). Another mutation in the termination codon, X654C, had previously been observed in cells of a patient (GM01898) whose phenotype could not be clearly classified as either Hurler or Hurler/Scheie (Bach et al., 1993).
In the study of 19 Japanese MPS I (607014) patients with various clinical phenotypes, Yamagishi et al. (1996) found that a 5-bp insertion between the T at nucleotide 704 and the C at nucleotide 705 accounted for 7 of 38 alleles (18%). This mutation had not been found in any Caucasian patients. It was associated with a specific haplotype, suggesting to the authors that the individuals with the mutation derived from a common ancestor. Homozygosity of the 704ins5 mutation was associated with a severe phenotype.
Lee et al. (2004) found the 704ins5 mutation in 4 of 10 unrelated Korean patients with MPS I. All occurred in compound heterozygous state in patients with Hurler syndrome (607014).
In the study of 19 Japanese MPS I patients with various clinical phenotypes, Yamagishi et al. (1996) found that the R89Q mutation accounted for 9 of 38 alleles (24%). Homozygosity for the R89Q mutation was associated with a mild phenotype. Compound heterozygosity for this and the 704ins5 mutation (252800.0014) produced an intermediate phenotype (607015). Haplotype analysis using polymorphisms linked to the IDUA locus demonstrated that the mutation occurred on a specific haplotype, suggesting to the authors that individuals with the mutation derived from a common ancestor. Of 3 homozygotes, 1 died of congestive heart failure at the age of 48 years. One of the heterozygotes died of the same at 31 years. She was 117 cm tall. Scott et al. (1993) had previously described the R89Q mutation in compound heterozygous state with the W402X mutation (252800.0001) in Caucasian Hurler syndrome (607014) patients.
In a healthy female, Aronovich et al. (1996) found compound heterozygosity for the W402X mutation (252800.0001) and a new IDUA mutation, A300T. Although fibroblasts from the patient demonstrated normal glycosaminoglycan metabolism, enzyme studies using artificial substrate showed very low levels of alpha-L-iduronidase activity. This was said to have been the first IDUA pseudodeficiency gene to be elucidated at the molecular level.
In an 18-year-old Chinese patient with an intermediate phenotype consistent with Hurler/Scheie syndrome (607015), Lee-Chen et al. (1999) identified homozygosity for an arg619-to-gly (R619G) mutation due to a C-to-G transversion at nucleotide 1943.
Lee-Chen and Wang (1997) identified homozygosity for a thr364-to-met (T364M) mutation in the IDUA gene product in a 10-year-old Chinese patient with the Hurler/Scheie syndrome (607015).
In a Chinese patient with Hurler/Scheie syndrome (607015), Teng et al. (2000) identified compound heterozygosity for a maternal allele with a leu346-to-arg (L346R; 252800.0020) mutation (T-to-G transversion in codon 346) and a paternal allele with a C-to-G transversion at position -3 of the 3-prime splice acceptor site of intron 2. In transfected COS-7 cells, L346R showed no appreciable IDUA activity, although it did not cause an apparent reduction in IDUA mRNA or protein level. The splice acceptor site mutation profoundly affected normal splicing leading to a very unstable mRNA. Expression of IDUA cDNA containing the mutated acceptor splice site showed trace amounts of enzyme activity (1.6% of normal activity). The results provided further support for the importance of cytosine at the -3 position in RNA processing. The patient reported by Teng et al. (2000) was 12 years old with short stature, macrocephaly, coarse face, corneal clouding, skeletal deformities, and hepatosplenomegaly, but normal intelligence. Other mild clinical features included hearing impairment, tracheal stenosis, hypertrophic cardiomyopathy, obstructive-type sleep apnea, adenoid hyperplasia, tonsil hypertrophy, umbilical hernia, anemia,
For discussion of the leu346-to-arg (L346R) mutation in the IDUA gene that was found in compound heterozygous state in a patient with Hurler/Scheie syndrome (607015) by Teng et al. (2000), see 252800.0019.
Lee et al. (2004) found the L346R mutation in 6 of 10 unrelated Korean patients with MPS I, 4 with Hurler syndrome (607014) and 2 with Hurler/Scheie syndrome.
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