GM02016

GM02016 Fibroblast

Description:

HURLER-SCHEIE SYNDROME
CYTOCHROME P450, SUBFAMILY IID, POLYPEPTIDE 6; CYP2D6
CYTOCHROME P450, SUBFAMILY IIC, POLYPEPTIDE 19; CYP2C19
CYTOCHROME P450, SUBFAMILY IIC, POLYPEPTIDE 9; CYP2C9
VITAMIN K EPOXIDE REDUCTASE COMPLEX, SUBUNIT 1; VKORC1
UDP-GLYCOSYLTRANSFERASE 1 FAMILY, POLYPEPTIDE A1; UGT1A1
ALPHA-L-IDURONIDASE; IDUA

Affected:

No

Sex:

Female

Age:

35 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Lysosomal Storage Diseases
Pharmacogenetics
GeT-RM Samples

Class

Disorders of Carbohydrate Metabolism

Alternate IDs

GM17042 [HURLER-SCHEIE SYNDROME]

GM17332 [HURLER-SCHEIE SYNDROME]

Cell Type

Fibroblast

Transformant

Untransformed

Race

White

Ethnicity

MIDDLE EASTERN; ARAB;

Family Member

Relation to Proband

mother

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically unaffected mother of affected child (GM01898); The following datasets were obtained and reported by the GeT-RM program: HLA variants (HLA-A*02:01/*30:02, HLA-B*53:01/*58:01, HLA-C*04:01/*07:01, HLA-DRB1*08:04/*14:01, HLA-DQB1*04:02/*05:01); pharmacogenomic variants ( CYP2D6*2XN/*17, CYP2C19*1/*2, CYP2C9*1/*1, VKORC1*WT/-1639G>A, UGT1A1*1/*1).

Characterizations

PDL at Freeze

5.22

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase Isoenzyme Electrophoresis

Pharmacogenomics Panel

For pharmacogenetic variants please click here: GeT-RM PGx Search

HLA TYPING

For HLA variants please click here: HLA Panel

Gene

CYP2D6

Chromosomal Location

22q13.1

Allelic Variant 1

T107I; R296C; S486T; DEBRISOQUINE, POOR METABOLISM OF

Identified Mutation

THR107ILE, ARG296CYS, AND SER486THR; This allelic variant is also known as CYP2D6*17 or CYP2D6(Z). Oscarson et al (Mol Pharmacol 52(6):1034-40, 1997) found that in many black African populations, the capacity for CYP2D6-dependent drug metabolism is generally reduced. A specific variant of the CYP2D6 gene (CYP2D6*17) that carries three functional mutations (T107I, R296C, and S486T) has been found to be present in Zimbabwean subjects with impaired CYP2D6-dependent hydroxylase activity.

Gene

IDUA

Chromosomal Location

4p16.3

Allelic Variant 1

252800.0005; HURLER SYNDROME

Identified Mutation

GLY409ARG AND TER654CYS; In a patient with Hurler syndrome in a consanguineous Muslim Arab family in Gaza, Bach et al. (1993) observed homozygosity for an IDUA allele containing 2 amino acid substitutions: a G-to-C transversion in exon 9 converting codon 409 from GGG (gly) to CGG (arg), and an A-to-T transversion in the termination codon 654 (TGA), converting it to a cys (TGT) residue. The cDNA sequence predicted an extension of 38 amino acids before the next termination codon was reached. Both mutations were found in heterozygous form in the DNA of each parent. Expression of cDNA mutagenized at one or both positions showed that gly409-to-arg caused a reduction of less than half the alpha-L-iduronidase activity, whereas the ter-to-cys mutation reduced activity by 98% compared with expression of normal cDNA.

Gene

CYP2D6

Chromosomal Location

22q13.1

Allelic Variant 2

124030.0008; CODEINE, ULTRARAPID METABOLISM OF

Identified Mutation

DUP; Gasche et al (New Eng J Med 351:2827-2831, 2004) described a patient who had developed life-threatening opioid intoxication after he was given small doses of codeine for the treatment of cough associated with bilateral pneumonia. CYP2D6 genotyping showed 3 or more functioning alleles, as a result of gene duplication, resulting in high levels of morphine and morphine-6 glucuronide.

Phenotypic Data

Remarks

Publications

Pratt VM, Turner A, Broeckel U, Dawson DB, Gaedigk A, Lynnes TC, Medeiros EB, Moyer AM, Requesens D, Ventrini F, Kalman LV, Characterization of Reference Materials for CYP2C9, CYP2C19, VKORC1, CYP2C Cluster Variant, GGCX, and Other Pharmacogenetic Alleles with an Association for Molecular Pathology (AMP) Pharmacogenetics Working Group Tier 2 Status - A GeT-RM Collaborative Project The Journal of molecular diagnostics : JMD: 2021

PubMed ID: 34020041

Ramudo-Cela L, López-Martí JM, Colmeiro-Echeberría D, De-Uña-Iglesias D, Santomé-Collazo JL, Monserrat-Iglesias L, Development and validation of a next-generation sequencing panel for clinical pharmacogenetics Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria44:243-253 2020

PubMed ID: 33156743

Scott SA, Scott ER, Seki Y, Chen AJ, Wallsten R, Owusu Obeng A, Botton MR, Cody N, Shi H, Zhao G, Brake P, Nicoletti P, Yang Y, Delio M, Shi L, Kornreich R, Schadt EE, Edelmann L, Development and Analytical Validation of a 29 Gene Clinical Pharmacogenetic Genotyping Panel: Multi-Ethnic Allele and Copy Number Variant Detection Clinical and translational science14:204-213 2020

PubMed ID: 32931151

Bettinotti MP1, Ferriola D2, Duke JL2, Mosbruger TL2, Tairis N2, Jennings L3, Kalman LV4, Monos D5., Characterization of 108 Genomic DNA Reference Materials for 11 Human Leukocyte Antigen Loci: A GeT-RM Collaborative Project. Journal of Molecular Diagnostics18:30111-30119 2018

PubMed ID: 29959025

Swart M, Stansberry WM, Pratt VM, Medeiros EB, Kiel PJ, Shen F, Schneider BP, Skaar TC, Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology The Journal of molecular diagnostics : JMD21:491-502 2018

PubMed ID: 30794985

Langaee T, Hamadeh I, Chapman AB, Gums JG, Johnson JA, A novel simple method for determining CYP2D6 gene copy number and identifying allele(s) with duplication/multiplication PloS one10:e0113808 2014

PubMed ID: 25625348

Lee CC, McMillin GA, Babic N, Melis R, Yeo KT, Evaluation of a CYP2C19 genotype panel on the GenMark eSensor® platform and the comparison to the Autogenomics Infiniti™ and Luminex CYP2C19 panels Clinica chimica acta; international journal of clinical chemistry412(11-12):133-7 2010

PubMed ID: 21385571

Pratt VM, Zehnbauer B, Wilson JA, Baak R, Babic N, Bettinotti M, Buller A, Butz K, Campbell M, Civalier C, El-Badry A, Farkas DH, Lyon E, Mandal S, McKinney J, Muralidharan K, Noll L, Sander T, Shabbeer J, Smith C, Telatar M, Toji L, Vairavan A, Vance C, Weck KE, Wu AH, Yeo KT, Zeller M, and Kalman L., Characterization of 107 Genomic DNA Reference Materials for CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1 J Mol Diagn12(6):835-46 2010

PubMed ID: 20889555

Jurevic RJ, Bai M, Chadwick RB, White TC, Dale BA, Single-nucleotide polymorphisms (SNPs) in human beta-defensin 1: high-throughput SNP assays and association with Candida carriage in type I diabetics and nondiabetic controls. J Clin Microbiol41(1):90-6 2003

PubMed ID: 12517831

Bach G, Moskowitz SM, Tieu PT, Matynia A, Neufeld EF, Molecular analysis of Hurler syndrome in Druze and Muslim Arab patients in Israel: multiple allelic mutations of the IDUA gene in a small geographic area American journal of human genetics53:330-8 1993

PubMed ID: 8328452