Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism.

Abstract:

:The debrisoquine/sparteine polymorphism is associated with a clinically important genetic deficiency of oxidative drug metabolism. From 5% to 10% of Caucasians designated as poor metabolizers (PMs) of the debrisoquine/sparteine polymorphism have a severely impaired capacity to metabolize more than 25 therapeutically used drugs. The impaired drug metabolism in PMs is due to the absence of cytochrome P450IID6 protein. The gene controlling the P450IID6 protein, CYP2D6, is located on the long arm of chromosome 22. A pseudogene CYP2D8P and a related gene CYP2D7 are located upstream from CYP2D6. This gene locus is highly polymorphic. After digestion of genomic DNA with XbaI endonuclease, restriction fragments of 11.5 kb and 44 kb represent mutant alleles of the cytochrome CYP2D6 gene locus associated with the PM phenotype. In order to elucidate the molecular mechanism of the mutant allele reflected by the XbaI 11.5-kb fragment, a genomic library was constructed from leukocyte DNA of one individual homozygous for this fragment and screened with the human IID6 cDNA. The CYP2D genes were isolated and characterized by restriction mapping and partial sequencing. We demonstrate that the mutant 11.5-kb allele results from a deletion involving the entire functional CYP2D6 gene. This result provides an explanation for the total absence of P450IID6 protein in the liver of these PMs.

journal_name

Am J Hum Genet

authors

Gaedigk A,Blum M,Gaedigk R,Eichelbaum M,Meyer UA

subject

Has Abstract

pub_date

1991-05-01 00:00:00

pages

943-50

issue

5

eissn

0002-9297

issn

1537-6605

journal_volume

48

pub_type

杂志文章
  • A population-based study of autosomal-recessive disease-causing mutations in a founder population.

    abstract::The decreasing cost of whole-genome and whole-exome sequencing has resulted in a renaissance for identifying Mendelian disease mutations, and for the first time it is possible to survey the distribution and characteristics of these mutations in large population samples. We conducted carrier screening for all autosomal...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2012.08.007

    authors: Chong JX,Ouwenga R,Anderson RL,Waggoner DJ,Ober C

    更新日期:2012-10-05 00:00:00

  • A "disproportion" between the frequency of rare electropmorphs and enzyme deficiency variants in Amerindians.

    abstract::Our previous studies have revealed a higher frequency of nonpolymorphic electrophoretic variants in blood samples from Amerindians than in similar samples from Caucasians and Japanese. Our present study finds, by contrast, that the frequency of deficiency variants of 11 erythrocyte enzymes, sampled in nine Amerindian ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Mohrenweiser HW,Neel JV

    更新日期:1984-05-01 00:00:00

  • Estimating kinship in admixed populations.

    abstract::Genome-wide association studies (GWASs) are commonly used for the mapping of genetic loci that influence complex traits. A problem that is often encountered in both population-based and family-based GWASs is that of identifying cryptic relatedness and population stratification because it is well known that failure to ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2012.05.024

    authors: Thornton T,Tang H,Hoffmann TJ,Ochs-Balcom HM,Caan BJ,Risch N

    更新日期:2012-07-13 00:00:00

  • Relationship estimation by Markov-process models in a sib-pair linkage study.

    abstract::The results of sib-pair linkage studies may be compromised if a substantial number of putative sib pairs are not actually sib pairs. For classification of pairs in a sib-pair genome scan, I propose multipoint methods that are based on a Markov-process model of allele sharing along the chromosome. These methods can be ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302360

    authors: Olson JM

    更新日期:1999-05-01 00:00:00

  • A collection of ordered tetranucleotide-repeat markers from the human genome. The Utah Marker Development Group.

    abstract::A collection of 1,069 human PCR-based genetic markers has been developed, and their distribution over the 22 autosomes and the X chromosome has been determined. Each marker was developed around a short-tandem-repeat DNA sequence. The majority (85%) of the markers described here were selected to contain tetranucleotide...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors:

    更新日期:1995-09-01 00:00:00

  • Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family.

    abstract::We report here the characterization of a large Chinese family with maternally transmitted aminoglycoside-induced and nonsyndromic deafness. In the absence of aminoglycosides, some matrilineal relatives in this family exhibited late-onset/progressive deafness, with a wide range of severity and age at onset. Notably, th...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/381133

    authors: Zhao H,Li R,Wang Q,Yan Q,Deng JH,Han D,Bai Y,Young WY,Guan MX

    更新日期:2004-01-01 00:00:00

  • A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents.

    abstract::Sensorineural deafness and retinitis pigmentosa (RP) are the hallmarks of Usher syndrome (USH) but are also prominent features in peroxisomal biogenesis defects (PBDs); both are autosomal recessively inherited. The firstborn son of unrelated parents, who both had sensorineural deafness and RP diagnosed as USH, present...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/339766

    authors: Raas-Rothschild A,Wanders RJ,Mooijer PA,Gootjes J,Waterham HR,Gutman A,Suzuki Y,Shimozawa N,Kondo N,Eshel G,Espeel M,Roels F,Korman SH

    更新日期:2002-04-01 00:00:00

  • Segregation of all four major fibrillar collagen genes in the Marfan syndrome.

    abstract::Linkage markers at or close to the genes encoding the three major fibrillar collagens were used to analyze the segregation of these loci in six pedigrees with dominantly inherited Marfan syndrome. Four pedigrees were discordant at one of the Type I collagen loci (COL1A2), and, of these, two were discordant at the othe...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Ogilvie DJ,Wordsworth BP,Priestley LM,Dalgleish R,Schmidtke J,Zoll B,Sykes BC

    更新日期:1987-12-01 00:00:00

  • Characterization of a spontaneous mutation to a beta-thalassemia allele.

    abstract::We have studied a nuclear family containing a single child with severe beta-thalassemia intermedia, a Greek-Cypriot mother with hematological findings of beta-thalassemia trait, and a Polish father who is hematologically normal. Since both the child and her father were heterozygous for a DNA polymorphism within the be...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Kazazian HH Jr,Orkin SH,Boehm CD,Goff SC,Wong C,Dowling CE,Newburger PE,Knowlton RG,Brown V,Donis-Keller H

    更新日期:1986-06-01 00:00:00

  • Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans.

    abstract::Congenital heart defects (CHDs) are among the most common birth defects in humans (incidence 8-10 per 1,000 live births). Although their etiology is often poorly understood, most are considered to arise from multifactorial influences, including environmental and genetic components, as well as from less common syndromi...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/522890

    authors: Karkera JD,Lee JS,Roessler E,Banerjee-Basu S,Ouspenskaia MV,Mez J,Goldmuntz E,Bowers P,Towbin J,Belmont JW,Baxevanis AD,Schier AF,Muenke M

    更新日期:2007-11-01 00:00:00

  • An evaluation of three statistics of structured exploratory data analysis.

    abstract::The power of structured exploratory data analysis (SEDA) to discriminate among major genic, polygenic, and nongenetic determination of phenotypes was investigated using computer simulation. Three classes of SEDA indices (the major gene index, the offspring between parents function, and the midparent-child correlation ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Kammerer CM,MacCluer JW,Bridges JM

    更新日期:1984-01-01 00:00:00

  • Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L.

    abstract::Ataxia-pancytopenia (AP) syndrome is characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to marrow failure and myeloid leukemia, sometimes associated with monosomy 7. Here, in the four-generation family UW-AP, linkage analysis revealed four regions that provided the maximal LOD scor...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2016.04.009

    authors: Chen DH,Below JE,Shimamura A,Keel SB,Matsushita M,Wolff J,Sul Y,Bonkowski E,Castella M,Taniguchi T,Nickerson D,Papayannopoulou T,Bird TD,Raskind WH

    更新日期:2016-06-02 00:00:00

  • A population-based study of familial Alzheimer disease: linkage to chromosomes 14, 19, and 21.

    abstract::Linkage of Alzheimer disease (AD) to DNA markers on chromosomes 14, 19, and 21 was studied in 10 families in which the disease was apparently inherited as an autosomal dominant trait. Families were derived from a Dutch population-based epidemiologic study of early-onset AD. Although in all probands the onset of AD was...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: van Duijn CM,Hendriks L,Farrer LA,Backhovens H,Cruts M,Wehnert A,Hofman A,Van Broeckhoven C

    更新日期:1994-10-01 00:00:00

  • Testing for genetic linkage in families by a variance-components approach in the presence of genomic imprinting.

    abstract::Some genes that affect development and behavior in mammals are known to be imprinted; and > or = 1% of all mammalian genes are imprinted. Hence, incorporating an imprinting parameter into linkage analysis may increase the power to detect linkage for these traits. Here we propose theoretical justifications for a recent...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/338931

    authors: Shete S,Amos CI

    更新日期:2002-03-01 00:00:00

  • Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene.

    abstract::The human SNRPN (small nuclear ribonucleoprotein polypeptide N) gene is one of a gene family that encode proteins involved in pre-mRNA splicing and maps to the smallest deletion region involved in the Prader-Willi syndrome (PWS) within chromosome 15q11-q13. Paternal only expression of SNRPN has previously been demonst...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Glenn CC,Saitoh S,Jong MT,Filbrandt MM,Surti U,Driscoll DJ,Nicholls RD

    更新日期:1996-02-01 00:00:00

  • Deep Phenotyping on Electronic Health Records Facilitates Genetic Diagnosis by Clinical Exomes.

    abstract::Integration of detailed phenotype information with genetic data is well established to facilitate accurate diagnosis of hereditary disorders. As a rich source of phenotype information, electronic health records (EHRs) promise to empower diagnostic variant interpretation. However, how to accurately and efficiently extr...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2018.05.010

    authors: Son JH,Xie G,Yuan C,Ena L,Li Z,Goldstein A,Huang L,Wang L,Shen F,Liu H,Mehl K,Groopman EE,Marasa M,Kiryluk K,Gharavi AG,Chung WK,Hripcsak G,Friedman C,Weng C,Wang K

    更新日期:2018-07-05 00:00:00

  • The segregation of C-band polymorphisms on chromosomes 1, 9, and 16.

    abstract::Eleven normal families with at least four children were studied cytogenetically using the C-band technique to identify polymorphisms in the constitutive heterochromatin of chromosomes 1, 9 and 16. Thirteen individuals showed one or more variants in such chromosomes. The analysis of the segregation ratios in the 35 off...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Carnevale A,Ibañez BB,del Castillo V

    更新日期:1976-07-01 00:00:00

  • Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility.

    abstract::We recently reported that a sequence variant in the cell-cycle-checkpoint kinase CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer-susceptibility allele in noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2 variants confer susceptibility to breast cancer, we screened the full CHEK2 codi...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/373965

    authors: Schutte M,Seal S,Barfoot R,Meijers-Heijboer H,Wasielewski M,Evans DG,Eccles D,Meijers C,Lohman F,Klijn J,van den Ouweland A,Futreal PA,Nathanson KL,Weber BL,Easton DF,Stratton MR,Rahman N,Breast Cancer Linkage Consortiu

    更新日期:2003-04-01 00:00:00

  • Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.

    abstract::Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypica...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2017.10.010

    authors: Luscan R,Mechaussier S,Paul A,Tian G,Gérard X,Defoort-Dellhemmes S,Loundon N,Audo I,Bonnin S,LeGargasson JF,Dumont J,Goudin N,Garfa-Traoré M,Bras M,Pouliet A,Bessières B,Boddaert N,Sahel JA,Lyonnet S,Kaplan J,Cowa

    更新日期:2017-12-07 00:00:00

  • Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy.

    abstract::Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2020.03.001

    authors: Nguyen TTM,Murakami Y,Mobilio S,Niceta M,Zampino G,Philippe C,Moutton S,Zaki MS,James KN,Musaev D,Mu W,Baranano K,Nance JR,Rosenfeld JA,Braverman N,Ciolfi A,Millan F,Person RE,Bruel AL,Thauvin-Robinet C,Ververi A

    更新日期:2020-04-02 00:00:00

  • A cell hybrid and recombinant DNA library that facilitate identification of polymorphic loci in the vicinity of the Huntington disease gene.

    abstract::Somatic cell hybrids were selected that retain a derivative chromosome 5 from an individual in which the p15.1-pter segment of chromosome 5 is replaced with the p15.1-pter segment of chromosome 4. Hybrids that retain this derivative chromosome exclusively were found to be positive for G8, a DNA marker closely linked t...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Wasmuth JJ,Carlock LR,Smith B,Immken LL

    更新日期:1986-09-01 00:00:00

  • An alternate method for demonstration of bisphosphoglyceromutase (DPGM) on starch gels.

    abstract::The phosphatase activity of bisphosphoglyceromutase (DPGM) was used to determine the phenotypes of the enzyme. DPGM was polymorphic in four Alaskan ethnic groups. ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Scott EM,Wright RC

    更新日期:1982-11-01 00:00:00

  • Recent developments in genomewide association scans: a workshop summary and review.

    abstract::With the imminent availability of ultra-high-volume genotyping platforms (on the order of 100,000-1,000,000 genotypes per sample) at a manageable cost, there is growing interest in the possibility of conducting genomewide association studies for a variety of diseases but, so far, little consensus on methods to design ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章,评审

    doi:10.1086/432962

    authors: Thomas DC,Haile RW,Duggan D

    更新日期:2005-09-01 00:00:00

  • Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features.

    abstract::The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysopho...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2016.07.019

    authors: Johansen A,Rosti RO,Musaev D,Sticca E,Harripaul R,Zaki M,Çağlayan AO,Azam M,Sultan T,Froukh T,Reis A,Popp B,Ahmed I,John P,Ayub M,Ben-Omran T,Vincent JB,Gleeson JG,Abou Jamra R

    更新日期:2016-10-06 00:00:00

  • Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

    abstract::Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and i...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2020.07.006

    authors: Thomas M,Sakoda LC,Hoffmeister M,Rosenthal EA,Lee JK,van Duijnhoven FJB,Platz EA,Wu AH,Dampier CH,de la Chapelle A,Wolk A,Joshi AD,Burnett-Hartman A,Gsur A,Lindblom A,Castells A,Win AK,Namjou B,Van Guelpen B,Tangen

    更新日期:2020-09-03 00:00:00

  • The presence of two different infantile Tay-Sachs disease mutations in a Cajun population.

    abstract::A study was undertaken to characterize the mutation(s) responsible for Tay-Sachs disease (TSD) in a Cajun population in southwest Louisiana and to identify the origins of these mutations. Eleven of 12 infantile TSD alleles examined in six families had the beta-hexosaminidase A (Hex A) alpha-subunit exon 11 insertion m...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: McDowell GA,Mules EH,Fabacher P,Shapira E,Blitzer MG

    更新日期:1992-11-01 00:00:00

  • Allele-Specific QTL Fine Mapping with PLASMA.

    abstract::Although quantitative trait locus (QTL) associations have been identified for many molecular traits such as gene expression, it remains challenging to distinguish the causal nucleotide from nearby variants. In addition to traditional QTLs by association, allele-specific (AS) QTLs are a powerful measure of cis-regulati...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2019.12.011

    authors: Wang AT,Shetty A,O'Connor E,Bell C,Pomerantz MM,Freedman ML,Gusev A

    更新日期:2020-02-06 00:00:00

  • Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.

    abstract::Brachydactyly type B (BDB) is an autosomal dominant skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. Recently, heterozygous mutations of the orphan receptor tyrosine kinase (TK) ROR2, located within a distinct segment directly after the TK domain, have been shown to be responsible f...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/303084

    authors: Schwabe GC,Tinschert S,Buschow C,Meinecke P,Wolff G,Gillessen-Kaesbach G,Oldridge M,Wilkie AO,Kömec R,Mundlos S

    更新日期:2000-10-01 00:00:00

  • Lysinuric protein intolerance (LPI) gene maps to the long arm of chromosome 14.

    abstract::Lysinuric protein intolerance (LPI) is an autosomal recessive disease characterized by defective transport of cationic amino acids and by hyperammonemia. Linkage analysis in 20 Finnish LPI families assigned the LPI gene locus to the proximal long arm of chromosome 14. Recombinations placed the locus between framework ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/515457

    authors: Lauteala T,Sistonen P,Savontaus ML,Mykkänen J,Simell J,Lukkarinen M,Simell O,Aula P

    更新日期:1997-06-01 00:00:00

  • Imprinting effect in premature ovarian failure confined to paternally inherited fragile X premutations.

    abstract::Fragile X premutations are considered to be a risk factor for premature ovarian failure (POF), which is usually defined as menopause at age <40 years. Since premutations may be inherited from either the mother or the father, we evaluated the influence of the inheritance pattern on the duration of reproductive life in ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302774

    authors: Hundscheid RD,Sistermans EA,Thomas CM,Braat DD,Straatman H,Kiemeney LA,Oostra BA,Smits AP

    更新日期:2000-02-01 00:00:00