Transport, enzymatic activity, and stability of mutant sulfamidase (SGSH) identified in patients with mucopolysaccharidosis type III A.


:Mucopolysaccharidosis type IIIA (MPSIIIA) is an autosomal recessive lysosomal storage disease caused by mutations in the N-sulfoglucosamine sulfohydrolase gene (SGSH; encoding sulfamidase, also sulphamidase) leading to the lysosomal accumulation and urinary excretion of heparan sulfate. Considerable variation in the onset and severity of the clinical phenotype is observed. We report here on expression studies of four novel mutations: c.318C>A (p.Ser106Arg), c.488T>C (p.Leu163Pro), c.571G>A (p.Gly191Arg), and c.1207_1209delTAC (p.Tyr403del), and five previously known mutations: c.220C>T (p.Arg74Cys), c.697C>T (p.Arg233X), c.1297C>T (p.Arg433Trp), c.1026dupC (p.Leu343fsX158), and c.1135delG (p.Val379fsX33) identified in MPSIIIA patients. Transient expression of mutant sulfamidases in BHK or CHO cells revealed that all the mutants were enzymatically inactive with the exception of c.318C>A (p.Ser106Arg), which showed 3.3% activity of the expressed wild-type enzyme. Western blot analysis demonstrated that the amounts of expressed mutant sulfamidases were significantly reduced compared with cells expressing wild type. No polypeptides were immunodetectable in extracts of cells transfected with the cDNA carrying the c.697C>T (p.Arg233X) nonsense mutation. In vitro translation and pulse-chase experiments showed that rapid degradation rather than a decrease in synthesis is responsible for the low, steady-state level of the mutant proteins in cells. The amounts of secreted mutant precursor forms, the cellular stability, the proteolytic processing, and data from double-label immunofluorescence microscopy suggest that the degradation of the majority of newly synthesized c.220C>T (p.Arg74Cys), c.571G>A (p.Gly191Arg), c.1297C>T (p.Arg433Trp), c.1026dupC (p.Leu343fsX158), and c.1135delG (p.Val379fsX33) mutant proteins probably occurs in the ER, whereas c.488T>C (p.Leu163Pro) mutant protein showed instability in the lysosomes.


Hum Mutat


Human mutation


Muschol N,Storch S,Ballhausen D,Beesley C,Westermann JC,Gal A,Ullrich K,Hopwood JJ,Winchester B,Braulke T





Has Abstract


2004-06-01 00:00:00












  • Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217

    abstract::Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/ bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 9 familie...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Taillandier A,Zurutuza L,Muller F,Simon-Bouy B,Serre JL,Bird L,Brenner R,Boute O,Cousin J,Gaillard D,Heidemann PH,Steinmann B,Wallot M,Mornet E

    更新日期:1999-01-01 00:00:00

  • GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK.

    abstract::We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual di...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Au PYB,You J,Caluseriu O,Schwartzentruber J,Majewski J,Bernier FP,Ferguson M,Care for Rare Canada Consortium.,Valle D,Parboosingh JS,Sobreira N,Innes AM,Kline AD

    更新日期:2015-10-01 00:00:00

  • Highly sensitive mutation screening by REF with low concentrations of urea: A blinded analysis of a 2-kb region of the p53 gene reveals two common haplotypes.

    abstract::Restriction endonuclease fingerprinting (REF), a hybrid modification of single-strand conformation polymorphism (SSCP) and restriction endonuclease digestion, has been used previously to detect mutations in 1- to 2-kb segments of DNA. This paper demonstrates that fragment resolution, and thus sensitivity of REF, can b...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Feng J,Buzin CH,Tang SH,Scaringe WA,Sommer SS

    更新日期:1999-01-01 00:00:00

  • Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia.

    abstract::The Ataxia Telangiectasia Mutation (ATM) gene is mutated in the rare recessive syndrome Ataxia Telangiectasia (AT), which is characterized by cerebellar degeneration, immunodeficiency, and cancer predisposition. In this study, 41 AT families from Denmark, Finland, Norway, and Sweden were screened for ATM mutations. Th...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Laake K,Jansen L,Hahnemann JM,Brondum-Nielsen K,Lönnqvist T,Kääriäinen H,Sankila R,Lähdesmäki A,Hammarström L,Yuen J,Tretli S,Heiberg A,Olsen JH,Tucker M,Kleinerman R,Børresen-Dale AL

    更新日期:2000-09-01 00:00:00

  • EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO.

    abstract::Impairment of translation initiation and its regulation within the integrated stress response (ISR) and related unfolded-protein response has been identified as a cause of several multisystemic syndromes. Here, we link MEHMO syndrome, whose genetic etiology was unknown, to this group of disorders. MEHMO is a rare X-li...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Skopkova M,Hennig F,Shin BS,Turner CE,Stanikova D,Brennerova K,Stanik J,Fischer U,Henden L,Müller U,Steinberger D,Leshinsky-Silver E,Bottani A,Kurdiova T,Ukropec J,Nyitrayova O,Kolnikova M,Klimes I,Borck G,Bahlo M,

    更新日期:2017-04-01 00:00:00

  • Splicing mutations, mainly IVS6-1(G>T), account for 70% of fumarylacetoacetate hydrolase (FAH) gene alterations, including 7 novel mutations, in a survey of 29 tyrosinemia type I patients.

    abstract::Hereditary tyrosinemia type I (HTI) is an autosomal recessive disease characterized by a deficiency in fumarylacetoacetate hydrolase (FAH) activity. In this work, the FAH genotype was established in a group of 29 HTI patients, most of them from the Mediterranean area. We identified seven novel mutations-IVS8-1(G>A, IV...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Arranz JA,Piñol F,Kozak L,Pérez-Cerdá C,Cormand B,Ugarte M,Riudor E

    更新日期:2002-09-01 00:00:00

  • Sequence diversity of KIAA0027/MLC1: are megalencephalic leukoencephalopathy and schizophrenia allelic disorders?

    abstract::The aim of the study is to validate the etiological role of KIAA0027/MLC1 in childhood-onset megalencephalic leukoencephalopathy with subcortical cysts (MLC) and in schizophrenia, particularly the catatonic subtype, which were reported to be allelic diseases. Among a series of five patients with MLC, four mutant allel...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Rubie C,Lichtner P,Gärtner J,Siekiera M,Uziel G,Kohlmann B,Kohlschütter A,Meitinger T,Stöber G,Bettecken T

    更新日期:2003-01-01 00:00:00

  • Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene.

    abstract::Patients with pyridoxine dependent epilepsy (PDE) present with early-onset seizures resistant to common anticonvulsants. According to the benefit of pyridoxine (vitamin B(6)) and recurrence of seizures on pyridoxine withdrawal, patients so far have been classified as having definite, probable, or possible PDE. Recentl...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Plecko B,Paul K,Paschke E,Stoeckler-Ipsiroglu S,Struys E,Jakobs C,Hartmann H,Luecke T,di Capua M,Korenke C,Hikel C,Reutershahn E,Freilinger M,Baumeister F,Bosch F,Erwa W

    更新日期:2007-01-01 00:00:00

  • Pancreatic insufficiency and pulmonary disease in German and Slavic cystic fibrosis patients with the R347P mutation.

    abstract::Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR) that codes for a cAMP-regulated chloride channel. The R347P is a missense mutation located within the first membrane spanning domain (MSD1) of the CFTR protein. This mutation occurs with an overal...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Varon R,Stuhrmann M,Macek M Jr,Kufardjieva A,Angelicheva D,Magdorf K,Jordanova A,Savov A,Wahn U,Macek M

    更新日期:1995-01-01 00:00:00

  • BRCA2 germline mutations in Cypriot patients with familial breast/ovarian cancer.

    abstract::Germline mutations in the BRCA2 gene have been shown to be associated with familial female and male breast cancer. Mutations occur throughout the entire coding region of the gene, and there is considerable ethnic and geographical diversity in the deleterious mutations detected in different populations. No data exist o...

    journal_title:Human mutation

    pub_type: 杂志文章,多中心研究


    authors: Hadjisavvas A,Charalambous E,Adamou A,Christodoulou CG,Kyriacou K

    更新日期:2003-02-01 00:00:00

  • Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.

    abstract::We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both gene...

    journal_title:Human mutation

    pub_type: 杂志文章,多中心研究


    authors: Nurden AT,Pillois X,Fiore M,Alessi MC,Bonduel M,Dreyfus M,Goudemand J,Gruel Y,Benabdallah-Guerida S,Latger-Cannard V,Négrier C,Nugent D,Oiron RD,Rand ML,Sié P,Trossaert M,Alberio L,Martins N,Sirvain-Trukniewicz P,Co

    更新日期:2015-05-01 00:00:00

  • Familial Mediterranean fever: Penetrance of the p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=] genotypes.

    abstract::The penetrance of the p.[Met694Val];[Met694Val] genotype of pyrin in adult familial Mediterranean fever (FMF) patients is close to 100%. Disease penetrance of the p.[Met694Val];[Glu148Gln] genotype (M694V/E148Q), and the heterozygous p.[Met694Val];[=] genotype is unknown. A difference in the penetrance of the latter t...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Eyal O,Shinar Y,Pras M,Pras E

    更新日期:2020-11-01 00:00:00

  • An online locus-specific mutation database for familial hypertrophic cardiomyopathy.

    abstract::The aim of this locus-specific mutation database was to provide an online resource that contains summarised and updated information on familial hypertrophic cardiomyopathy (FHC)-associated mutations and related data, for researchers and clinicians. It also serves as a means of publishing previously unpublished data, w...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Fung DC,Yu B,Littlejohn T,Trent RJ

    更新日期:1999-01-01 00:00:00

  • Whole genome sequencing and mutation rate analysis of trios with paternal dioxin exposure.

    abstract::2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) or dioxin, is commonly considered the most toxic man-made substance. Dioxin exposure impacts human health and diseases, birth defects and teratogenesis were frequently observed in children of persons who have been exposed to dioxin. However, the impact of dioxin on human muta...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Ton ND,Nakagawa H,Ha NH,Duong NT,Nhung VP,Hien LTT,Hue HTT,Hoang NH,Wong JH,Nakano K,Maejima K,Sasaki-Oku A,Tsunoda T,Fujimoto A,Van Hai N

    更新日期:2018-10-01 00:00:00

  • Systematic evaluation of the effect of common SNPs on pre-mRNA splicing.

    abstract::The evolutionary and biomedical importance of differential mRNA splicing is well established. Numerous studies have assessed patterns of differential splicing in different genes and correlated these patterns to the genotypes for adjacent single-nucleotide polymorphisms (SNPs). Here, we have chosen a reverse approach a...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: ElSharawy A,Hundrieser B,Brosch M,Wittig M,Huse K,Platzer M,Becker A,Simon M,Rosenstiel P,Schreiber S,Krawczak M,Hampe J

    更新日期:2009-04-01 00:00:00

  • Screening practices for mutations in the CFTR gene ABCC7.

    abstract::Cystic fibrosis transmembrane conductance regulator (CFTR) gene studies are now one of the most frequent activities in clinical molecular genetics laboratories. The number of requests is growing, owing to the increasingly wide range of recognized CFTR gene diseases (cystic fibrosis, congenital bilateral absence of the...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Girodon-Boulandet E,Cazeneuve C,Goossens M

    更新日期:2000-01-01 00:00:00

  • Denaturing HPLC analysis of DNA deletions and insertions.

    abstract::Denaturing HPLC (DHPLC) is a useful technique for the fast screening of known and unknown heterozygous gene mutations. Most DNA mutations causing genetic disorders consist of nucleotide substitutions, but insertions and deletions occur, albeit less frequently. The heteroduplexes with insertions/deletions have gaps tha...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Cremonesi L,Stenirri S,Fermo I,Paroni R,Ferrari M,Cazzola M,Arosio P

    更新日期:2003-07-01 00:00:00

  • MouseFinder: Candidate disease genes from mouse phenotype data.

    abstract::Mouse phenotype data represents a valuable resource for the identification of disease-associated genes, especially where the molecular basis is unknown and there is no clue to the candidate gene's function, pathway involvement or expression pattern. However, until recently these data have not been systematically used ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Chen CK,Mungall CJ,Gkoutos GV,Doelken SC,Köhler S,Ruef BJ,Smith C,Westerfield M,Robinson PN,Lewis SE,Schofield PN,Smedley D

    更新日期:2012-05-01 00:00:00

  • GRIN database: A unified and manually curated repertoire of GRIN variants.

    abstract::Glutamatergic neurotransmission is crucial for brain development, wiring neuronal function, and synaptic plasticity mechanisms. Recent genetic studies showed the existence of autosomal dominant de novo GRIN gene variants associated with GRIN-related disorders (GRDs), a rare pediatric neurological disorder caused by N-...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: García-Recio A,Santos-Gómez A,Soto D,Julia-Palacios N,García-Cazorla À,Altafaj X,Olivella M

    更新日期:2020-11-30 00:00:00

  • Databases in the area of pharmacogenetics.

    abstract::In the area of pharmacogenetics and personalized health care it is obvious that databases, providing important information of the occurrence and consequences of variant genes encoding drug metabolizing enzymes, drug transporters, drug targets, and other proteins of importance for drug response or toxicity, are of crit...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Sim SC,Altman RB,Ingelman-Sundberg M

    更新日期:2011-05-01 00:00:00

  • In vitro mutations in dihydrofolate reductase that confer resistance to methotrexate: potential for clinical application.

    abstract::Mammalian cells cultured in the presence of the chemotherapeutic agent, methotrexate, develop resistance to this drug. Sometimes this is due to mutations in the gene for dihydrofolate reductase, the primary target of methotrexate. However, it has not been possible to link such polymorphism to resistance of neoplastic ...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Blakley RL,Sorrentino BP

    更新日期:1998-01-01 00:00:00

  • Five novel mutations in the lysosomal sialidase gene (NEU1) in type II sialidosis patients and assessment of their impact on enzyme activity and intracellular targeting using adenovirus-mediated expression.

    abstract::Sialidosis is an autosomal recessive disease resulting from a deficiency of lysosomal sialidase. Type II sialidosis is a rare disease characterized clinically by hydrops fetalis, hepatosplenomegaly, and severe psychomotor retardation. Genomic DNA from four unrelated sialidosis patients was screened for mutations withi...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pattison S,Pankarican M,Rupar CA,Graham FL,Igdoura SA

    更新日期:2004-01-01 00:00:00

  • Identification of novel polymorphisms in the pM5 and MRP1 (ABCC1) genes at locus 16p13.1 and exclusion of both genes as responsible for pseudoxanthoma elasticum.

    abstract::Pseudoxanthoma elasticum (PXE) is an inherited systemic disorder of connective tissue, characterized by progressive calcification of the elastic fibers in the eye, the skin, and the cardiovascular system. The PXE locus has been mapped to chromosome 16p13.1, and was recently further refined to a 500 kb-region, containi...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Perdu J,Germain DP

    更新日期:2001-01-01 00:00:00

  • An overview and update of ATP7A mutations leading to Menkes disease and occipital horn syndrome.

    abstract::Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar "kinky" hair, are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males. M...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Tümer Z

    更新日期:2013-03-01 00:00:00

  • A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.

    abstract::The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Schepers D,Tortora G,Morisaki H,MacCarrick G,Lindsay M,Liang D,Mehta SG,Hague J,Verhagen J,van de Laar I,Wessels M,Detisch Y,van Haelst M,Baas A,Lichtenbelt K,Braun K,van der Linde D,Roos-Hesselink J,McGillivray G,M

    更新日期:2018-05-01 00:00:00

  • Two-round coamplification at lower denaturation temperature-PCR (COLD-PCR)-based sanger sequencing identifies a novel spectrum of low-level mutations in lung adenocarcinoma.

    abstract::Reliable identification of cancer-related mutations in TP53 is often problematic, as these mutations can be randomly distributed throughout numerous codons and their relative abundance in clinical samples can fall below the sensitivity limits of conventional sequencing. To ensure the highest sensitivity in mutation de...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Li J,Milbury CA,Li C,Makrigiorgos GM

    更新日期:2009-11-01 00:00:00

  • Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene.

    abstract::Congenital erythropoietic porphyria (CEP) is an autosomal recessive inborn error of metabolism that results from the markedly deficient activity of the fourth enzyme in the heme biosynthetic pathway, uroporphyrinogen III synthase (URO-synthase). To date, 17 mutations have been described including 11 missense, one nons...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Xu W,Astrin KH,Desnick RJ

    更新日期:1996-01-01 00:00:00

  • Guide and links to online genetic and genomic educational resources, valuable for all levels.

    abstract::There is a well-recognized growing need for improved access to online genetic and genomics education for professionals, students, teachers, and the public. Numerous individual online genetic and genomic educational resources have been developed, but many are difficult to identify or locate when required. Consequently,...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Tobias AP,Tobias ES

    更新日期:2020-12-01 00:00:00

  • Capillary electrophoresis analysis of conventional splicing assays: IARC analytical and clinical classification of 31 BRCA2 genetic variants.

    abstract::Rare sequence variants in "high-risk" disease genes, often referred as unclassified variants (UVs), pose a serious challenge to genetic testing. However, UVs resulting in splicing alterations can be readily assessed by in vitro assays. Unfortunately, analytical and clinical interpretation of these assays is often chal...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: de Garibay GR,Acedo A,García-Casado Z,Gutiérrez-Enríquez S,Tosar A,Romero A,Garre P,Llort G,Thomassen M,Díez O,Pérez-Segura P,Díaz-Rubio E,Velasco EA,Caldés T,de la Hoya M

    更新日期:2014-01-01 00:00:00

  • Assessment of predicted enzymatic activity of α-N-acetylglucosaminidase variants of unknown significance for CAGI 2016.

    abstract::The NAGLU challenge of the fourth edition of the Critical Assessment of Genome Interpretation experiment (CAGI4) in 2016, invited participants to predict the impact of variants of unknown significance (VUS) on the enzymatic activity of the lysosomal hydrolase α-N-acetylglucosaminidase (NAGLU). Deficiencies in NAGLU ac...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Clark WT,Kasak L,Bakolitsa C,Hu Z,Andreoletti G,Babbi G,Bromberg Y,Casadio R,Dunbrack R,Folkman L,Ford CT,Jones D,Katsonis P,Kundu K,Lichtarge O,Martelli PL,Mooney SD,Nodzak C,Pal LR,Radivojac P,Savojardo C,Shi

    更新日期:2019-09-01 00:00:00