GM01256

GM01256 Fibroblast

Description:

SCHEIE SYNDROME
ALPHA-L-IDURONIDASE; IDUA

Affected:

Yes

Sex:

Male

Age:

12 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases

Class

Disorders of Carbohydrate Metabolism

Cell Type

Fibroblast

Transformant

Untransformed

Race

White

Relation to Proband

proband

Confirmation

Molecular characterization after cell line submission to CCR

Species

Homo sapiens

Common Name

Human

Remarks

Deficient Alpha-L-Iduronidase; Scheie syndrome; compound heterozygote: a G>A transition in intron 5, in position -7 from exon 6 (IVS5AS-7G>A) and TGG>TAG at nucleotide 1293 in exon 9 of the IDUA gene [Trp402Ter (W402X)]

Characterizations

PDL at Freeze

6.55

Passage Frozen

L-iduronidase

According to the submitter, biochemical test results for this subject showed decreased enzyme activity. EC Number: 3.2.1.76

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by LINE assay

Gene

IDUA

Chromosomal Location

4p16.3

Allelic Variant 1

252800.0004; SCHEIE SYNDROME

Identified Mutation

IVS5AS, G>A, -7; In the fibroblast strain GM01323 derived from the index case of the Scheie syndrome reported by McKusick et al. [Medicine (Baltimore) 44: 445 (1965)] and in a second cell line, GM01256, Moskowitz et al. [Hum Mutat 2: 71 (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., Genomics 13: 1311 (1992)].

Gene

IDUA

Chromosomal Location

4p16.3

Allelic Variant 2

252800.0001; HURLER SYNDROME

Identified Mutation

TRP402TER; Scott et al. [Genomics 13: 1311 (1992)] found that 31% of MPS I alleles in a study of 64 patients with Hurler syndrome had a trp402-to-ter 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 trp-402 codon (TGG) to a stop codon (TAG); translation was terminated approximately two-thirds of the way through the 653-amino acid IDUA protein. Significantly, the index case of Scheie syndrome reported by McKusick et al. [Medicine (Baltimore) 44: 445 (1965)] (M.McC., GM01323), 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, GM01323 fibroblasts had no detectable IDUA protein using 2 different IDUA monoclonal antibodies. 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 (see 252800.0004), this proved to be the case.

Phenotypic Data

Remarks

Publications

Swaroop M1, Brooks MJ2, Gieser L2, Swaroop A2, Zheng W1., Patient iPSC-derived neural stem cells exhibit phenotypes in concordance with the clinical severity of Mucopolysaccharidosis I Human Molecular Genetics: 2018

PubMed ID: 30052969

Makino E, Klodnitsky H, Leonard J, Lillie J, Lund TC, Marshall J, Nietupski J, Orchard PJ, Miller WP, Phaneuf C, Tietz D, Varban ML, Donovan M, Belenki A, Fast, sensitive method for trisaccharide biomarker detection in mucopolysaccharidosis type 1 Scientific reports8:3681 2017

PubMed ID: 29487322

Moskowitz SM, Tieu PT, Neufeld EF, Mutation in Scheie syndrome (MPS IS): a G-->A transition creates new splice site in intron 5 of one IDUA allele. Hum Mutat2:141-4 1993

PubMed ID: 8318992