Propionic acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed in Escherichia coli.


:Deficiency of propionyl-CoA carboxylase (PCC) results in propionic acidemia, an autosomal recessive disorder characterized by ketoacidosis sufficiently severe to cause neonatal death. PCC is involved in the catabolism of branched-chain amino acids, odd-chain fatty acids, and cholesterol. The enzyme is a biotin-dependent mitochondrial protein composed of two heterologous subunits arranged into an 800-kDa alpha(6 )beta(6) dodecameric structure. Approximately 60 mutations have been reported in the nuclear genes PCCA and PCCB that encode the two PCC subunits. The vast majority of these mutations have not been examined at the protein level. We present an initial characterization of 13 mutations located in exons 1, 3-7, and 12-14 of PCCB. After expression in E. coli, these recombinant mutant enzymes were analyzed for stability, biotinylation, alpha-beta subunit interaction, and activity. Our results show a functional dichotomy in these PCCB mutations with some mutants (R44P, S106R, G131R, G198D, V205D, I408del, and M442T) capable of varying degrees of assembly but forming catalytically inactive PCC proteins. Other PCCB mutants (R165W, E168K, D178H, P228L, and R410W) that are PCC deficient in patient-derived fibroblasts, were found to be capable of expressing wild-type level PCC activity when assembled in our chaperone-assisted E. coli expression system. This result indicates that these mutations exert their pathogenic effect due to an inability to assemble correctly in patients' cells. This initial screen has identified a range of mutant PCC proteins that are sufficiently stable to be purified and subsequently used for structure-function analysis to further elucidate the complex relationship between genotype and phenotype in propionic acidemia.


Hum Mutat


Human mutation


Chloupkova M,Maclean KN,Alkhateeb A,Kraus JP





Has Abstract


2002-06-01 00:00:00












  • Genomic convergence to identify candidate genes for Alzheimer disease on chromosome 10.

    abstract::A broad region of chromosome 10 (chr10) has engendered continued interest in the etiology of late-onset Alzheimer Disease (LOAD) from both linkage and candidate gene studies. However, there is a very extensive heterogeneity on chr10. We converged linkage analysis and gene expression data using the concept of genomic c...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Liang X,Slifer M,Martin ER,Schnetz-Boutaud N,Bartlett J,Anderson B,Züchner S,Gwirtsman H,Gilbert JR,Pericak-Vance MA,Haines JL

    更新日期:2009-03-01 00:00:00

  • Correction of a Cystic Fibrosis Splicing Mutation by Antisense Oligonucleotides.

    abstract::Cystic fibrosis (CF), the most common life-threatening genetic disease in Caucasians, is caused by ∼2,000 different mutations in the CF transmembrane conductance regulator (CFTR) gene. A significant fraction of these (∼13%) affect pre-mRNA splicing for which novel therapies have been somewhat neglected. We have previo...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Igreja S,Clarke LA,Botelho HM,Marques L,Amaral MD

    更新日期:2016-02-01 00:00:00

  • The distribution of constitutional and somatic mutations in the neurofibromatosis 2 gene.

    abstract::Constitutional heterozygous inactivating mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene cause the autosomal dominant disease NF2, and biallelic inactivating somatic NF2 mutations are found in a high proportion of unilateral sporadic vestibular schwannoma (USVS) and sporadic meningioma. We surveyed th...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Baser ME,Contributors to the International NF2 Mutation Database.

    更新日期:2006-04-01 00:00:00

  • Homocystinuria in the Arab population of Israel: identification of two novel mutations using DGGE analysis.

    abstract::This study describes, for the first time, a thorough genetic investigation in Israeli Arab homocystinuric patients. By using a DGGE methodology and sequencing we were able to identify the disease causing mutation in all. Of the mutations that were detected, two are novel: a 785C>G transversion in exon 7 (T262R) and a ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Gat-Yablonski G,Mandel H,Fowler B,Taleb O,Sela BA

    更新日期:2000-10-01 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

  • Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy.

    abstract::Influenza-associated encephalopathy (IAE) is characterized by persistent high fever, febrile convulsions, severe brain edema, and high mortality in otherwise apparently healthy individuals. We have reported that a large proportion of patients suffering from disabling or fatal IAE, with transiently elevated serum acylc...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Yao D,Mizuguchi H,Yamaguchi M,Yamada H,Chida J,Shikata K,Kido H

    更新日期:2008-05-01 00:00:00

  • Novel SCA19/22-associated KCND3 mutations disrupt human KV 4.3 protein biosynthesis and channel gating.

    abstract::Mutations in the human voltage-gated K+ channel subunit KV 4.3-encoding KCND3 gene have been associated with the autosomal dominant neurodegenerative disorder spinocerebellar ataxia types 19 and 22 (SCA19/22). The precise pathophysiology underlying the dominant inheritance pattern of SCA19/22 remains elusive. Using ce...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Hsiao CT,Fu SJ,Liu YT,Lu YH,Zhong CY,Tang CY,Soong BW,Jeng CJ

    更新日期:2019-11-01 00:00:00

  • Three novel mutations and twelve polymorphisms identified in the USH2A gene in Israeli USH2 families.

    abstract::The Usher syndromes are autosomal recessive hereditary disorders characterized by hearing impairment and progressive visual loss due to Retinitis Pigmentosa (RP). Moderate to severe sensorineural hearing loss and progressive RP characterizes Usher syndrome type IIa (USH2A), which maps to the long arm of chromosome 1q4...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Adato A,Weston MD,Berry A,Kimberling WJ,Bonne-Tamir A

    更新日期:2000-04-01 00:00:00

  • Discovery of genetic profiles impacting response to chemotherapy: application to gemcitabine.

    abstract::Chemotherapy is a major treatment modality for individuals affected by cancer. Currently, a number of genome-based technologies are being adopted to identify genes associated with drug response; however, large-scale genetic association applications are still limited. Here we describe a novel strategy based on the gene...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Jarjanazi H,Kiefer J,Savas S,Briollais L,Tuzmen S,Pabalan N,Ibrahim-Zada I,Mousses S,Ozcelik H

    更新日期:2008-04-01 00:00:00

  • wKinMut-2: Identification and Interpretation of Pathogenic Variants in Human Protein Kinases.

    abstract::Most genomic alterations are tolerated while only a minor fraction disrupts molecular function sufficiently to drive disease. Protein kinases play a central biological function and the functional consequences of their variants are abundantly characterized. However, this heterogeneous information is often scattered acr...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Vazquez M,Pons T,Brunak S,Valencia A,Izarzugaza JM

    更新日期:2016-01-01 00:00:00

  • Transcript dosage effect in familial adenomatous polyposis: model offered by two kindreds with exon 9 APC gene mutations.

    abstract::Analysis of genotype-phenotype correlations in familial adenomatous polyposis (FAP) patients demonstrated that the phenotypic heterogeneity of FAP is partly related to the mutation site. We investigated the molecular basis for the difference in severity of colorectal disease observed comparing FAP patients from two ki...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Curia MC,Esposito DL,Aceto G,Palmirotta R,Crognale S,Valanzano R,Ficari F,Tonelli F,Battista P,Mariani-Costantini R,Cama A

    更新日期:1998-01-01 00:00:00

  • In silico analysis of missense substitutions using sequence-alignment based methods.

    abstract::Genetic testing for mutations in high-risk cancer susceptibility genes often reveals missense substitutions that are not easily classified as pathogenic or neutral. Among the methods that can help in their classification are computational analyses. Predictions of pathogenic vs. neutral, or the probability that a varia...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Tavtigian SV,Greenblatt MS,Lesueur F,Byrnes GB,IARC Unclassified Genetic Variants Working Group.

    更新日期:2008-11-01 00:00:00

  • Novel Tay-Sachs disease mutations from China.

    abstract::We describe three HEXA mutations associated with infantile Tay-Sachs disease (TSD) in three unrelated nonconsanguineous Chinese families. Novel mutations were found in two of these families. The third is a previously reported mutation (G-->A transition at nt 1444) (Nakano et al., 1988). Direct sequencing of PCR produc...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Akalin N,Shi HP,Vavougios G,Hechtman P,Lo W,Scriver CR,Mahuran D,Kaplan F

    更新日期:1992-01-01 00:00:00

  • A frequent somatic mutation in CD274 3'-UTR leads to protein over-expression in gastric cancer by disrupting miR-570 binding.

    abstract::Inhibitory costimulatory molecule CD274 expresses in various cancers and contributes to cancer immune evasion by inhibiting T cell activation and proliferation, yet the regulatory mechanisms for CD274 overexpression in cancers are poorly understood. In this study, we discovered a novel mechanism of CD274 expression re...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Wang W,Sun J,Li F,Li R,Gu Y,Liu C,Yang P,Zhu M,Chen L,Tian W,Zhou H,Mao Y,Zhang L,Jiang J,Wu C,Hua D,Chen W,Lu B,Ju J,Zhang X

    更新日期:2012-03-01 00:00:00

  • Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy.

    abstract::Nemaline myopathy (NM) is a clinically and genetically heterogeneous disorder of skeletal muscle caused by mutations in at least five different genes encoding thin filament proteins of the striated muscle sarcomere. We have previously described 18 different mutations in the last 42 exons of the nebulin gene (NEB) in 1...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lehtokari VL,Pelin K,Sandbacka M,Ranta S,Donner K,Muntoni F,Sewry C,Angelini C,Bushby K,Van den Bergh P,Iannaccone S,Laing NG,Wallgren-Pettersson C

    更新日期:2006-09-01 00:00:00

  • Tissue distribution of the ND4/11778 mutation in heteroplasmic lineages with Leber hereditary optic neuropathy.

    abstract::Leber hereditary optic neuropathy (LHON) is a maternally inherited eye disease most commonly caused by mitochondrial DNA (mtDNA) point mutation at position 11778, 3460, or 14484. Approximately 14% of families show heteroplasmy for the pathogenic mutations but little is known about the mutational burden in different ti...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Juvonen V,Nikoskelainen E,Lamminen T,Penttinen M,Aula P,Savontaus ML

    更新日期:1997-01-01 00:00:00

  • Aberrant COL11A1 splicing causes prelingual autosomal dominant nonsyndromic hearing loss in the DFNA37 locus.

    abstract::Alpha-chain collagen molecules encoded by genes that include COL11A1 are essential for skeletal, ocular, and auditory function. COL11A1 variants have been reported in syndromes involving these organ systems. However, a description of the complete clinical spectrum is lacking, as evidenced by a recent association of au...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Rad A,Schade-Mann T,Gamerdinger P,Yanus GA,Schulte B,Müller M,Imyanitov EN,Biskup S,Löwenheim H,Tropitzsch A,Vona B

    更新日期:2020-11-10 00:00:00

  • Two ATM variants and breast cancer risk.

    abstract::The ATM gene is mutated in ataxia-telangiectasia (AT). Heterozygote female relatives of AT cases have a 2-7fold increased risk of breast cancer. We previously reported high risks of breast cancer associated with certain ATM variants. To estimate the risks more precisely, we have examined two ATM variants, c.1066-6T>G ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Thompson D,Antoniou AC,Jenkins M,Marsh A,Chen X,Wayne T,Tesoriero A,Milne R,Spurdle A,Thorstenson Y,Southey M,Giles GG,Khanna KK,Sambrook J,Oefner P,Goldgar D,Hopper JL,Easton D,Chenevix-Trench G,KConFab Investigato

    更新日期:2005-06-01 00:00:00

  • Mutation nomenclature in practice: findings and recommendations from the cystic fibrosis external quality assessment scheme.

    abstract::Currently, two nomenclature systems are in use to describe sequence variants for cystic fibrosis: the established traditional nomenclature system and the more recent Human Genome Variation Society (HGVS) nomenclature system. We have evaluated the use of both systems in the laboratory reports of 217 participants in the...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Berwouts S,Morris MA,Girodon E,Schwarz M,Stuhrmann M,Dequeker E

    更新日期:2011-11-01 00:00:00

  • A mutation of SCN1B associated with GEFS+ causes functional and maturation defects of the voltage-dependent sodium channel.

    abstract::Voltage-dependent sodium channels are responsible of the rising phase of the action potential in excitable cells. These integral membrane proteins are composed of a pore-forming α-subunit, and one or more auxiliary β subunits. Mutation p.Asp25Asn (D25N; c.73G > A) of the β1 subunit, coded by the gene SCN1B, has been r...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Baroni D,Picco C,Moran O

    更新日期:2018-10-01 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

  • A functional polymorphism in the pre-miR-146a gene is associated with the risk of nonsyndromic orofacial cleft.

    abstract::microRNAs (miRNAs) are widely involved in craniofacial development, and genetic variants of miRNAs may be associated with the risk of nonsyndromic orofacial cleft (NSOC). Here, we systematically selected five single nucleotide polymorphisms (SNPs) of miRNAs and investigated the associations between these variants and ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pan Y,Li D,Lou S,Zhang C,Du Y,Jiang H,Zhang W,Ma L,Wang L

    更新日期:2018-05-01 00:00:00

  • Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype.

    abstract::The most common mutations in type I collagen causing types II-IV osteogenesis imperfecta (OI) result in substitution for glycine in a Gly-Xaa-Yaa triplet by another amino acid. We delineated a Y-position substitution in a small pedigree with a combined OI/Ehlers-Danlos Syndrome (EDS) phenotype, characterized by modera...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Cabral WA,Makareeva E,Letocha AD,Scribanu N,Fertala A,Steplewski A,Keene DR,Persikov AV,Leikin S,Marini JC

    更新日期:2007-04-01 00:00:00

  • Absence of exon 15 BRAF germline mutations in familial melanoma.

    abstract::We have analyzed DNA from peripheral blood of 42 cases of familial melanoma for germline mutations in exon 15 of the BRAF gene. No evidence of mutation was found. We have also analyzed DNA extracted from secondary melanoma from two members of these families. These results were also negative. In addition we have search...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lang J,Boxer M,MacKie R

    更新日期:2003-03-01 00:00:00

  • Mutations in the Human Argininosuccinate Synthetase (ASS1) Gene, Impact on Patients, Common Changes, and Structural Considerations.

    abstract::Citrullinemia type 1 is an autosomal recessive urea cycle disorder caused by defects in the argininosuccinate synthetase (ASS) enzyme due to mutations in ASS1 gene. An impairment of ASS function can lead to a wide spectrum of phenotypes, from life-threatening neonatal hyperammonemia to a later onset with mild symptoms...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Diez-Fernandez C,Rüfenacht V,Häberle J

    更新日期:2017-05-01 00:00:00

  • Characterization of 17 novel endoglin mutations associated with hereditary hemorrhagic telangiectasia.

    abstract::Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a vascular dysplasia caused by mutations in the endoglin (ENG) gene and associated with epistaxis, telangiectases, and a high incidence of pulmonary arteriovenous malformations. To efficiently detect deletions and insertions, we optimized a quantitative multiplex ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Cymerman U,Vera S,Karabegovic A,Abdalla S,Letarte M

    更新日期:2003-05-01 00:00:00

  • Detecting false-positive signals in exome sequencing.

    abstract::Disease gene discovery has been transformed by affordable sequencing of exomes and genomes. Identification of disease-causing mutations requires sifting through a large number of sequence variants. A subset of the variants are unlikely to be good candidates for disease causation based on one or more of the following c...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Fuentes Fajardo KV,Adams D,NISC Comparative Sequencing Program.,Mason CE,Sincan M,Tifft C,Toro C,Boerkoel CF,Gahl W,Markello T

    更新日期:2012-04-01 00:00:00

  • Clinically relevant variants - identifying, collecting, interpreting, and disseminating: the 2013 annual scientific meeting of the Human Genome Variation Society.

    abstract::The dramatic advances in genetic sequencing technologies used in research laboratories are now entering the clinic, and applications of whole-genome and whole-exome sequencing to disease diagnosis, predisposition, and treatment will soon be commonplace. However, the standards and methods for identifying clinically rel...

    journal_title:Human mutation



    authors: Stanley CM,Sunyaev SR,Greenblatt MS,Oetting WS

    更新日期:2014-04-01 00:00:00

  • Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain.

    abstract::MUTYH-associated polyposis (MAP) is an adenomatous polyposis transmitted in an autosomal-recessive pattern, involving biallelic inactivation of the MUTYH gene. Loss of a functional MUTYH protein will result in the accumulation of G:T mismatched DNA caused by oxidative damage. Although p.Y179C and p.G396D are the two m...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Komine K,Shimodaira H,Takao M,Soeda H,Zhang X,Takahashi M,Ishioka C

    更新日期:2015-07-01 00:00:00

  • BBS genotype-phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition.

    abstract::Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, polydactyly, renal abnormalities, and cognitive impairment for which 15 causative genes have been identified. Here we present the results of a mutational analysis of our multiethnic cohort of 83 families (105 cases); 75.9% of t...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Deveault C,Billingsley G,Duncan JL,Bin J,Theal R,Vincent A,Fieggen KJ,Gerth C,Noordeh N,Traboulsi EI,Fishman GA,Chitayat D,Knueppel T,Millán JM,Munier FL,Kennedy D,Jacobson SG,Innes AM,Mitchell GA,Boycott K,Héon E

    更新日期:2011-06-01 00:00:00