Mutation analysis of iduronate-2-sulphatase gene in 24 patients with Hunter syndrome: Characterisation of 6 novel mutations

Hartog, Catherine; Fryer, Alan; Upadhyaya, Meena

doi:10.1002/(sici)1098-1004(1999)14:1<87::aid-humu14>3.0.co;2-n

Cited by 10 publications

(9 citation statements)

References 29 publications

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“…(Leu479Gln)DDDNovelIranFH8-P21.719.4Exon 11c.1599 G > Ap. (Trp533*)DDD 56 Subject originality unknownFH1-P11.410.0Exon 12c.1729T > Cp. (Trp577Arg)DDD 25,26 TurkeyFH2-P18.614.2FH7-P22.517.5FH17-P15.313.6Exon 14c.2001_2002delinsGTp.…”

Section: Resultsmentioning

confidence: 99%

The Genetic Spectrum of Familial Hypercholesterolemia (FH) in the Iranian Population

Fairoozy

Futema

Vakili

et al. 2017

Sci Rep

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Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with premature cardiovascular disease (CVD). Mutations in the LDLR, APOB, and PCSK9 genes are known to cause FH. In this study, we analysed the genetic spectrum of the disease in subjects from the Iranian population with a clinical diagnosis of FH. Samples were collected from 16 children and family members from five different cities of Iran. Probands were screened for mutations in the LDLR, APOB, and PCSK9 genes using next generation sequencing, with results confirmed by Sanger sequencing. The likely pathology of identified variants was examined using in silico tools. Of the probands, 14 had a clinical diagnosis of homozygous FH and two of heterozygous FH. No mutations were found in either APOB or PCSK9, but nine probands were homozygous for seven different LDLR mutations, with p.(Trp577Arg) occurring in three and p.Val806Glyfs*11 occurring in two patients. Two mutations were novel: p.(Leu479Gln) and p.(Glu668*). Seven probands with a clinical diagnosis of FH were mutation negative. This pilot study, integrating clinical and molecular-based techniques, begins to elucidate the FH heterogeneity and the mutation spectrum in the Iranian population. Such information is important for future disease management and cost savings.

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Section: Resultsmentioning

confidence: 99%

The Genetic Spectrum of Familial Hypercholesterolemia (FH) in the Iranian Population

Fairoozy

Futema

Vakili

et al. 2017

Sci Rep

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“…The single base-substitutions were the cause of 3 missense, 2 nonsense mutations, an alteration of the splicing site and a silent mutation. Two missense mutations, R468Q (Bunge et al, 1992;Sukegawa et al, 1995;Karsten et al, 1998) and R88H Gort et al, 1998;Karsten et al, 1998) were found in 7 patients with a severe phenotype (H3, H7, H8, H12, H20, H23, H55), whereas the E521K missense mutation (Lissens et al, 1997) was responsible for the intermediate phenotype of the patient H119; the 2 nonsense mutations, R443X (Bunge et al, 1992;Sukegawa et al,1992;Froisart et al, 1993;Rathmann et al, 1996;Gort et al, 1998;Vafiadaki et al, 1998;Hartog et al, 1999 ) and R8X ( Vafiadaki et al, 1998) were detected in 2 patients ( H47 and H26 respectively ) with the intermediate form of the disease, and the alteration of the splicing G374G (Bunge et al, 1992;Flomen et al, 1992;Goldenfum et al, 1996;Rathmann et al, 1996;Hartog et al 1999) in 2 patients (H48, H61) with intermediate phenotype; the silent mutation T146T was detected in one case (H55) coexisting with the missense mutation R468Q (Bunge et al, 1992) whereas in two cases (H9, H67) was found, as an individual mutation as previously reported by Flomen et al, 1992 andAronovich et al, 1993. Since the T146T mutation has frequently been described as a polymorphism site Li et al, 1995) we sequenced the total cDNA as well as the genomic exon IV, where the alteration is located, including the surrounding intronic sequences of both patients H9 and H67, no evidence of other alterations was found.…”

Section: Resultsmentioning

confidence: 99%

“…To date, more than 200 different mutations have been reported in the IDS gene including missense and nonsense mutations, splice-site alterations, insertions, deletions, and rearrangements. (Wilson et al, 1991;Palmieri et al, 1992;Hopwood et al, 1993;Karsten et al, 1998;Vafiadaki et al, 1998;Hartog et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of 40 Italian patients with mucopolysaccharidosis type II: New mutations in the iduronate-2-sulfatase (IDS) gene

et al. 2001

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Mucopolysaccharidosis type II (MPS2, or Hunter syndrome), rare X-linked lysosomal storage disorder, results from deleterious mutations in the iduronate-2-sulfatase (IDS) gene. We report here the mutational analysis of a total of 40 unrelated Italian MPS II patients ranging from mild to severe phenotype. We are able to assign the genotype to 29 of them (72.5%), identifying 22 different mutations, five of which are unpublished (c.533delTT, W12X, N265I, c.1131-1142del, c.1131-1305del). A total of 55.2% of the molecularly characterised patients resulted from missense mutations, 20.7% from nonsense mutations, and another 13.8% of patients from small deletions (<20pb) or splice mutations, whereas 10.3% of the cases carried major structural alterations such as large deletion and rearrangements. The results reported here support the evidence of the mutational heterogeneity of the IDS gene as well as the difficulty to correlate genotype and phenotype in the patients with MPSII. However, the molecular characterisation of the patients is advantageous, making the carrier detection feasible for the females in the family at risk and improving the reliability of prenatal diagnosis techniques. Moreover, it provides a good foundation for therapeutic strategies.

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“…In addition to these missense mutations, a unique point mutation, c.1122C>T (G374G), has been found in many other ethnicities, European countries, Russia, and Korea (Bunge et al 1993;Rathmann et al 1996;Gort et al 1998;Balzano et al 1998;Vafiadaki et al 1998;Karsten et al 1998;Hartog et al 1999;Filocamo et al 2001). This common mutation appears to relate mainly to the attenuated phenotype, as indicated in our structural analysis, but some patients showed severe manifestations.…”

Section: Discussionmentioning

confidence: 99%

Mutational and structural analysis of Japanese patients with mucopolysaccharidosis type II

Kato

Kuratsubo

et al. 2005

J Hum Genet

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We investigated mutations of the iduronate-2-sulfatase (I2S) gene and structural characteristics of I2S to clarify genotype/phenotype relationships in 18 Japanese patients with mucopolysaccharidosis type II. The I2S gene was analyzed in five patients with a severe phenotype and in 13 patients with an attenuated phenotype. The tertiary structural model of the human I2S was constructed by homology modeling using the arylsulfatase structure as a template. We identified four missense mutations and a nonsense mutation in the severe phenotype; four missense, two nonsense, three frame shifts, and one each of splice and amino acid deletion in the attenuated phenotype. Seven of them (L73del, Q75X, G140R, C171R, V401 fs, C422 fs, and H441 fs) were novel mutations. Structural analysis indicated that the residues of the mutations found in the severe phenotype would have direct interactions with the active site residues or should break the hydrophobic core domain of I2S, whereas residues of the missense mutations found in the attenuated phenotype were located in the peripheral region. In addition, effects by deletion or frameshift mutations could also be interpreted by the structure. Structural analysis of mutant proteins would help in understanding the genotype/phenotype relationships of Hunter disease.

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Mutation analysis of iduronate-2-sulphatase gene in 24 patients with Hunter syndrome: Characterisation of 6 novel mutations

Cited by 10 publications

References 29 publications

The Genetic Spectrum of Familial Hypercholesterolemia (FH) in the Iranian Population

The Genetic Spectrum of Familial Hypercholesterolemia (FH) in the Iranian Population

Molecular analysis of 40 Italian patients with mucopolysaccharidosis type II: New mutations in the iduronate-2-sulfatase (IDS) gene

Mutational and structural analysis of Japanese patients with mucopolysaccharidosis type II

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