Identification and characterisation of mutations underlying Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB)

Lee-Chen, GJ; Lin, Shuo; Chuang, CK; Kt, Hsiao; Cf, Huang; Lien, Wan‐Ching

doi:10.1136/jmg.39.2.e3

Cited by 19 publications

(17 citation statements)

References 13 publications

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“…Y309C was found in heterozygous form in a patient from the United Kingdom. This mutation has been reported previously in heterozygous form in a Chinese patient (Lee-Chen et al 2002). R130C has also been reported in a Chinese patient (Lee-Chen et al 2002), and in our study it was found in one of the Hong Kong Chinese patients, suggestive of prevalence in the Chinese population.…”

Section: Discussionsupporting

confidence: 72%

“…Since the cloning of the NAGLU gene, 106 mutations have been described, consisting of 63 missense, 9 nonsense, 18 deletion, 14 insertion and 2 splice site mutations (Beesley et al 1998(Beesley et al , 2004Bunge et al 1999;Coll et al 2001;Emre et al 2002;Lee-Chen et al 2002;Schmidtchen et al 1998;Tanaka et al 2002;Tessitore et al 2000;Weber et al 1999;Yogalingam and Hopwood 2001 (review);Zhao et al 1996Zhao et al , 1998. A small number of recurrent mutations have been found in several different populations, but the majority of mutations are confined to individual families.…”

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confidence: 96%

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Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB)

Beesley

Jackson

Young

et al. 2005

J of Inher Metab Disea

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Sanfilippo syndrome type B (mucopolysaccharidosis IIIB) is an autosomal recessive disease that is caused by the deficiency of the lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). NAGLU is involved in the degradation of the glycosaminoglycan (GAG) heparan sulphate, and a deficiency results in the accumulation of partially degraded GAGs inside lysosomes. Early clinical symptoms include hyperactivity, aggressiveness and delayed development, followed by progressive mental deterioration, although there are a small number of late-onset attenuated cases. The gene for NAGLU has been fully characterized and we report the molecular analysis of 18 Sanfilippo B families. In total, 34 of the 36 mutant alleles were characterized in this study and 20 different mutations were identified including 8 novel changes (R38W, V77G, 407-410del4, 703delT, A246P, Y335C, 1487delT, E639X). The four novel missense mutations were transiently expressed in Chinese hamster ovary cells and all were shown to decrease the NAGLU activity markedly, although A246P did produce 12.7% residual enzyme activity.

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Section: Discussionsupporting

confidence: 72%

mentioning

confidence: 96%

Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB)

Beesley

Jackson

Young

et al. 2005

J of Inher Metab Disea

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“…Polymerase chain reaction (PCR) of IDS exons including adjacent intronic regions was carried out with the primers and under the conditions listed in Table 1. PCR products were mixed with an equal volume of 95% formamide buffer and electrophoresed for single-strand conformation polymorphism (SSCP) and heteroduplex analyses as previously described (Lee-Chen et al 2002). Fragments showing single-strand mobility shifts or heteroduplex bands were sequenced directly by using a MegaBACE analyzer.…”

Section: Mutation Analysismentioning

confidence: 99%

“…Total RNA was isolated from human cultured fibroblasts and reverse transcription/PCR (RT-PCR) amplification carried out as previously described (Lee-Chen et al 2002). The sense and antisense primers used for amplification of IDS cDNA are shown in Table 1.…”

Section: Cdna Constructsmentioning

confidence: 99%

Expression studies of mutations underlying Taiwanese Hunter syndrome (mucopolysaccharidosis type II)

Chang

Lin

et al. 2004

Hum Genet

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Nearly 300 different mutations underlying mucopolysaccharidosis type II (MPS II) have been identified worldwide. To investigate the molecular lesions underlying Taiwanese MPS II, probands and families were identified and screened for iduronate-2-sulfatase (IDS) mutation by single-strand conformation polymorphism and DNA sequencing. Five novel and five previously reported mutations were found. Together with those previously reported, a total of 17 identified missense, small deletion, and nonsense mutations were further characterized by transient expression studies. Transfection of COS-7 cells by the mutated cDNA did not yield active enzyme, demonstrating the deleterious nature of the mutations. A 57% decrease in IDS mRNA level was seen with the 231del6 mutation. Among the 11 missense mutations examined, K347E substitution showed apparent normal maturation and targeting on immunoblot and confocal fluorescence microscopy examination. The other 10 missense mutations showed apparent normal precursor with little or reduced mature forms, indicating normal maturation but incorrect targeting of the mutant enzymes. Among the six deletion and nonsense mutations examined, 1055del12 and E521X showed abnormal maturation. The staining pattern of the truncated W267X and 1184delG proteins suggested retention within early vacuolar compartments. The mutated 231del6 and 1421delAG proteins were unstable and largely degraded. Molecular analysis of the IDS gene will clearly identify the cause of the disease within patients and allow antenatal and family studies. The further characterization of gene mutations may delineate their functional consequences on IDS activity and processing and may enable future studies of genotype-phenotype correlation to estimate a prognosis and to lead to possible therapeutic interventions.

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“…The genetic defect is caused by different mutations (deletion, splice-site, and point mutations) [8,[14][15][16]. Numerous mutations on different gene locations can be detected [17], as more than 45 mutations are found only in MPS VI [14,18], 31 in MPS IV [19] and seven in MPS type IIB (M. Sanfilippo B) [20]. This variety of mutations is thought to be responsible for the wide variation in clinical severity [15].…”

mentioning

confidence: 99%

Clinical and Neuroradiological Aspects of the Different Types

Müller‐Forell

Frenking²,

Amraoui³

et al. 2007

Clin Neuroradiol

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The different types (I-VII) of mucopolysaccharidoses (MPS), a hereditary lysosomal storage disorder where the enzyme defect leads to glycosaminoglycan deposits in different tissues, present with characteristic lesions of the central nervous system (CNS). This review reports the CT and MRI findings of patients suffering from mucopolysaccharidosis in the context with aspects of biochemistry, pathophysiology, histological findings and clinical course. Neuroradiological findings include hydrocephalus, focal or global brain atrophy, and spinal cord compression at the atlantoaxial joint. Cribriform white matter lesions, corresponding to mucopolysaccharide deposition in the enlarged perivascular space, combined with leukencephalopathy are found in about half of the patients. Another half of the patients show minor to severe myelopathy at the atlantoaxial joint due to cervical cord compression. These findings are observed mainly in patients with MPS type IV, but as well in nearly all patients with MPS type VI. In the literature brain involvement is described exclusively in MPS type I, II and III, but the authors show definite demyelination and widening of the perivascular space in a number of patients with MPS type VI, who additionally suffered from progressive visual deficits, caused by ocular and/or optic nerve involvement. ZusammenfassungDie verschiedenen Formen der Mukopolysaccharidosen (MPS), einer hereditären, lysosomalen Speicherkrankheit, die, bedingt durch einen Enzymdefekt, zu Glykosaminoglykanablagerungen in verschiedenen Geweben führt, weisen charakteristische Veränderungen des zentralen Nervensystems (ZNS) aus. In dieser Übersichtsarbeit werden die CT-und MRT-Befunde von Patienten mit Mukopolysaccharidosen in Zusammenhang mit biochemischen, pathophysiologischen und pathohistologischen Befunden sowie charakteristischen klinischen Symptomen und im Verlauf vorgestellt. Die neuroradiologischen Befunde des ZNS weisen neben einem Hydrozephalus, einer fokalen und/oder globalen Atrophie auch eine medulläre Kompression am kraniozervikalen Übergang auf. Hinzu kommen erweiterte perivaskuläre Räume und Veränderungen der weißen Substanz. In jeweils etwa der Hälfte aller Patienten werden diese sog. cribriformen Läsionen (bedingt durch perivaskuläre Mukopolysaccharidablagerungen) und eine Leukenzephalopathie sowie eine hohe zervikale Myelonkompression mit unterschiedlich ausgeprägter Myelomalazie gefunden. Diese Befunde sind in erster Linie bei Patienten mit MPS IV, aber auch in der Mehrzahl der Patienten mit MPS VI zu finden. In der Literatur wird angegeben, dass eine ZNS-Beteiligung lediglich bei Patienten mit MPS I, II und III zu finden ist, die Autoren haben jedoch Demyelinisierung und erweiterte perivaskuläre Räume auch bei Patienten mit MPS VI nachgewiesen, die zusätzlich auch an progredienter Visusminderung litten, bedingt durch eine Beteiligung der Kornea und/oder des Nervus opticus. Schlüsselwörter: Mukopolysaccharidosen (MPS) · MR · Perivaskulärer Raum · Myelopathie · Leukenzephalopathie

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Identification and characterisation of mutations underlying Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB)

Cited by 19 publications

References 13 publications

Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB)

Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB)

Expression studies of mutations underlying Taiwanese Hunter syndrome (mucopolysaccharidosis type II)

Clinical and Neuroradiological Aspects of the Different Types

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