Mucopolysaccharidosis type II: Identification of 30 novel mutations among Latin American patients

Brusius-Facchin, Ana Carolina; Schwartz, Ida Vanessa Döederlein; Zimmer, Constantin; Ribeiro, Márcia Gonçalves; Acosta, Angelina Xavier; Horovitz, Dafne Dain Gandelman; Monlleó, Isabella Lopes; Fontes, Marshall Ítalo Barros; Fett‐Conte, Agnes Cristina; Sobrinho, Ruy P. Oliveira; Duarte, Andréa R.; Boy, R.; Mabe, Paulina; Ascurra, Marta; Michelena, Maria De; Tylee, Karen; Besley, G. T. N.; Garreton, M.C.V.; Giugliani, Roberto; Leistner-Segal, Sandra

doi:10.1016/j.ymgme.2013.08.011

Cited by 45 publications

(55 citation statements)

References 47 publications

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“…Specifically, the above mutations have also been found in the Asian population such as in Chinese and Japanese patients [4, 25, 26] presenting with the severe phenotype. The published nonsense mutations, p.Q75*, p.W109*, and p.R172*, were found in our patients with severe phenotypes and were in agreement with previous literature reports among Caucasian and Asian patients with Hunter syndrome in terms of their effects on phenotype [19, 20, 27–29]. Mutations introducing premature translation termination codons trigger nonsense-mediated decay, which prevents the synthesis of an abnormal protein, and have commonly been classified as severe mutations [4].…”

Section: Discussionsupporting

confidence: 93%

Clinical, biochemical and molecular characteristics of Filipino patients with mucopolysaccharidosis type II - Hunter syndrome

Chiong

Canson

Abacan

et al. 2017

Orphanet J Rare Dis

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BackgroundMucopolysaccharidosis type II, an X-linked recessive disorder is the most common lysosomal storage disease detected among Filipinos. This is a case series involving 23 male Filipino patients confirmed to have Hunter syndrome. The clinical and biochemical characteristics were obtained and mutation testing of the IDS gene was done on the probands and their female relatives.ResultsThe mean age of the patients was 11.28 (SD 4.10) years with an average symptom onset at 1.2 (SD 1.4) years. The mean age at biochemical diagnosis was 8 (SD 3.2) years. The early clinical characteristics were developmental delay, joint stiffness, coarse facies, recurrent respiratory tract infections, abdominal distention and hernia. Majority of the patients had joint contractures, severe intellectual disability, error of refraction, hearing loss and valvular regurgitation on subspecialists’ evaluation. The mean GAG concentration was 506.5 mg (SD 191.3)/grams creatinine while the mean plasma iduronate-2-sulfatase activity was 0.86 (SD 0.79) nmol/mg plasma/4 h. Fourteen (14) mutations were found: 6 missense (42.9%), 4 nonsense (28.6%), 2 frameshift (14.3%), 1 exon skipping at the cDNA level (7.1%), and 1 gross insertion (7.1%). Six (6) novel mutations were observed (43%): p.C422F, p.P86Rfs*44, p.Q121*, p.L209Wfs*4, p.T409R, and c.1461_1462insN[710].ConclusionThe age at diagnosis in this series was much delayed and majority of the patients presented with severe neurologic impairment. The results of the biochemical tests did not contribute to the phenotypic classification of patients. The effects of the mutations were consistent with the severe phenotype seen in the majority of the patients.

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Section: Discussionsupporting

confidence: 93%

Clinical, biochemical and molecular characteristics of Filipino patients with mucopolysaccharidosis type II - Hunter syndrome

Chiong

Canson

Abacan

et al. 2017

Orphanet J Rare Dis

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“…Some involved exon 3 of IDS; the premRNA region of this exon is particularly vulnerable to defects in splicing regulation. In the present work, functional analysis based on reporter minigenes was performed for two exon 3 nucleotide changes, c.257C N T [29][30][31] and c.241C N T [32], which confirmed these to be involved in exon 3 splicing dysregulation. Further, mutant minigene analysis and overexpression assays revealed that the SRSF2 (formerly SC35) and hnRNP E1 proteins might be involved in the use and repression of the constitutive 3′ splice site of exon 3 respectively.…”

Section: Introductionsupporting

confidence: 71%

“…Table 1 shows the genetic defects carried by the patients. Patient 1 was hemizygous for a nucleotide change in exon 3, c.241C NT (p.Q81X) already erroneously reported as p.Q80R by Brusius-Facchin et al [32]. A detailed analysis of the codon in the HGMD database (Professional 2014.3 Release) showed the mutation reported by these authors was, in fact, Q81X.…”

Section: Antisense Oligonucleotide Treatment and Analysismentioning

confidence: 93%

Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II

Matos

Gonçalves

Pinto

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Mucopolysaccharidosis II is a lysosomal storage disorder caused by mutations in the IDS gene, including exonic alterations associated with aberrant splicing. In the present work, cell-based splicing assays were performed to study the effects of two splicing mutations in exon 3 of IDS, i.e., c.241C>T and c.257C>T, whose presence activates a cryptic splice site in exon 3 and one in exon 8, i.e., c.1122C>T that despite being a synonymous mutation is responsible for the creation of a new splice site in exon 8 leading to a transcript shorter than usual. Mutant minigene analysis and overexpression assays revealed that SRSF2 and hnRNP E1 might be involved in the use and repression of the constitutive 3' splice site of exon 3 respectively. For the c.1122C>T the use of antisense therapy to correct the splicing defect was explored, but transfection of patient fibroblasts with antisense morpholino oligonucleotides (n=3) and a locked nucleic acid failed to abolish the abnormal transcript; indeed, it resulted in the appearance of yet another aberrant splicing product. Interestingly, the oligonucleotides transfection in control fibroblasts led to the appearance of the aberrant transcript observed in patients' cells after treatment, which shows that the oligonucleotides are masking an important cis-acting element for 5' splice site regulation of exon 8. These results highlight the importance of functional studies for understanding the pathogenic consequences of mis-splicing and highlight the difficulty in developing antisense therapies involving gene regions under complex splicing regulation.

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“…The patient described here is one of the youngest MPS II patients to have received HSCT so far; there is one patient reported to have been transplanted at 1.5 month [26]. Our described patient had the prediction of a severe phenotype proven both by the family history and the genotype [17], [18], [19].…”

Section: Discussionmentioning

confidence: 71%

“…Undetectable iduronate-2-sulphatase (I2S) activity and the familial p.Arg88His mutation on exon 3 (p.R88H) were detected in fibroblasts of the amniotic fluid. This is a missense mutation already reported and associated with the severe phenotype of MPS II [17], [18], [19].…”

Section: Case Reportmentioning

confidence: 79%

Early hematopoietic stem cell transplantation in a patient with severe mucopolysaccharidosis II: A 7 years follow-up

Barth¹,

Magalhães²,

Reis³

et al. 2017

Molecular Genetics and Metabolism Reports

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Mucopolysaccharidosis type II (MPS II - Hunter syndrome) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme iduronate-2 sulfatase (I2S), leading to the accumulation of the glycosaminoglycans, affecting multiple organs and systems. Enzyme replacement therapy does not cross the blood brain barrier, limiting results in neurological forms of the disease. Another option of treatment for severe MPS, hematopoietic stem cell transplantation (HSCT) has become the treatment of choice for the severe form of MPS type I, since it can preserve neurocognition when performed early in the course of the disease. To date, only few studies have examined the long-term outcomes of HSCT in patients with MPS II. We describe the seven-year follow-up of a prenatally diagnosed MPS II boy with positive family history of severe MPS form, submitted to HSCT with umbilical cord blood cells at 70 days of age. Engraftment after 30 days revealed mixed chimerism with 79% donor cells; after 7 years engraftment remains at 80%. I2S activity 30 days post-transplant was low in plasma and normal in leukocytes and the same pattern is observed to date. At age 7 years growth charts are normal and he is very healthy, although mild signs of dysostosis multiplex are present, as well as hearing loss. The neuropsychological evaluation (Wechsler Intelligence Scale for Children - Fourth Edition - WISC-IV), disclosed an IQ of 47. Despite this low measured IQ, the patient continues to show improvements in cognitive, language and motor skills, being quite functional. We believe that HSCT is a therapeutic option for MPS II patients with the severe phenotype, as it could preserve neurocognition or even halt neurodegeneration, provided strict selection criteria are followed.

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Mucopolysaccharidosis type II: Identification of 30 novel mutations among Latin American patients

Cited by 45 publications

References 47 publications

Clinical, biochemical and molecular characteristics of Filipino patients with mucopolysaccharidosis type II - Hunter syndrome

Clinical, biochemical and molecular characteristics of Filipino patients with mucopolysaccharidosis type II - Hunter syndrome

Functional analysis of splicing mutations in the IDS gene and the use of antisense oligonucleotides to exploit an alternative therapy for MPS II

Early hematopoietic stem cell transplantation in a patient with severe mucopolysaccharidosis II: A 7 years follow-up

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