Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity.


:Mutations in the parkin gene, encoding an E3 ubiquitin-protein ligase, are a frequent cause of autosomal recessive parkinsonism and are also involved in sporadic Parkinson's disease. Loss of Parkin function is thought to compromise the polyubiquitylation and proteasomal degradation of specific substrates, leading to their deleterious accumulation. Several studies have analyzed the effects of parkin gene mutations on the biochemical properties of the protein. However, the absence of a cell-free system for studying intrinsic Parkin activity has limited the interpretation of these studies. Here we describe the biochemical characterization of Parkin and 10 pathogenic variants carrying amino-acid substitutions throughout the sequence. Mutations in the RING fingers or the ubiquitin-like domain decreased the solubility of the protein in detergent and increased its tendency to form visible aggregates. None of the mutations studied compromised the binding of Parkin to a series of known protein partners/substrates. Moreover, only two variants with substitutions of conserved cysteine residues of the second RING finger were inactive in a purely in vitro ubiquitylation assay, demonstrating that loss of ligase activity is a minor pathogenic mechanism. Interestingly, in this in vitro assay, Parkin catalyzed the linkage of single ubiquitin molecules only, whereas the ubiquitin-protein ligases CHIP and Mdm2 promoted the formation of polyubiquitin chains. Similarly, in mammalian cells Parkin promoted the multimonoubiquitylation of its substrate p38, rather than its polyubiquitylation. Thus, Parkin may mediate polyubiquitylation or proteasome-independent monoubiquitylation depending on the protein context. The discovery of monoubiquitylated Parkin species in cells hints at a novel post-translational modification potentially involved in the regulation of Parkin function.


Hum Mol Genet


Human molecular genetics


Hampe C,Ardila-Osorio H,Fournier M,Brice A,Corti O




Has Abstract


2006-07-01 00:00:00














  • A window into third-generation sequencing.

    abstract::First- and second-generation sequencing technologies have led the way in revolutionizing the field of genomics and beyond, motivating an astonishing number of scientific advances, including enabling a more complete understanding of whole genome sequences and the information encoded therein, a more complete characteriz...

    journal_title:Human molecular genetics

    pub_type: 杂志文章,评审


    authors: Schadt EE,Turner S,Kasarskis A

    更新日期:2010-10-15 00:00:00

  • Characterization of four mutations in the neurofibromatosis type 1 gene by denaturing gradient gel electrophoresis (DGGE).

    abstract::Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders. The gene responsible for the disease has a very high mutation rate, approximately fifty per cent of NF1 patients appear to have a de novo mutation. The search for mutations is hampered by the large size of the NF1 gene and up to date, relati...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Valero MC,Velasco E,Moreno F,Hernández-Chico C

    更新日期:1994-04-01 00:00:00

  • The nystagmus-associated FRMD7 gene regulates neuronal outgrowth and development.

    abstract::Mutations in the gene encoding FERM domain-containing 7 protein (FRMD7) are recognized as an important cause of X-linked idiopathic infantile nystagmus (IIN). However, the precise role of FRMD7 and its involvement in the pathogenesis of IIN are not understood. In the present study, we have explored the role of FRMD7 i...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Betts-Henderson J,Bartesaghi S,Crosier M,Lindsay S,Chen HL,Salomoni P,Gottlob I,Nicotera P

    更新日期:2010-01-15 00:00:00

  • Genetic control of serum IgE levels and asthma: linkage and linkage disequilibrium studies in an isolated population.

    abstract::Immunoglobulin E (IgE) concentration in serum is elevated in atopic diseases such as asthma. A large genomic region on chromosome 5 has previously been implicated in the control of IgE levels and bronchial hyperreactivity and may, therefore, harbor genes predisposing to asthma. In an effort to confirm this linkage and...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Laitinen T,Kauppi P,Ignatius J,Ruotsalainen T,Daly MJ,Kääriäinen H,Kruglyak L,Laitinen H,de la Chapelle A,Lander ES,Laitinen LA,Kere J

    更新日期:1997-11-01 00:00:00

  • Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia.

    abstract::Mandibuloacral dysplasia (MAD; OMIM 248370) is a rare, genetically and phenotypically heterogeneous, autosomal recessive disorder characterized by skeletal abnormalities including hypoplasia of the mandible and clavicles, acro-osteolysis, cutaneous atrophy and lipodystrophy. A homozygous missense mutation, Arg527His, ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Agarwal AK,Fryns JP,Auchus RJ,Garg A

    更新日期:2003-08-15 00:00:00

  • Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy.

    abstract::Inherited peripheral neuropathies are a heterogeneous group of disorders that can affect patients of all ages. Children with inherited neuropathy often develop severe disability, but the genetic causes of recessive early-onset axonal neuropathies are not fully known. We have taken a whole-exome sequencing approach to ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Ylikallio E,Pöyhönen R,Zimon M,De Vriendt E,Hilander T,Paetau A,Jordanova A,Lönnqvist T,Tyynismaa H

    更新日期:2013-08-01 00:00:00

  • Skeletal muscle repair in a mouse model of nemaline myopathy.

    abstract::Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is a variably severe neuromuscular disorder for which no effective treatment is available. Although a number of genes have been identified in which mutations can cause NM, the pathogenetic mechanisms leading to the phenotypes are poorly unders...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Sanoudou D,Corbett MA,Han M,Ghoddusi M,Nguyen MA,Vlahovich N,Hardeman EC,Beggs AH

    更新日期:2006-09-01 00:00:00

  • Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy.

    abstract::Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer's disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and diverg...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Koller EJ,Gonzalez De La Cruz E,Machula T,Ibanez KR,Lin WL,Williams T,Riffe CJ,Ryu D,Strang KH,Liu X,Janus C,Golde TE,Dickson D,Giasson BI,Chakrabarty P

    更新日期:2019-10-01 00:00:00

  • Identification and characterization of functional risk variants for colorectal cancer mapping to chromosome 11q23.1.

    abstract::Genome-wide association studies of colorectal cancer (CRC) have identified a number of common variants associated with modest risk, including rs3802842 at chromosome 11q23.1. Several genes map to this region but rs3802842 does not map to any known transcribed or regulatory sequences. We reasoned, therefore, that rs380...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Biancolella M,Fortini BK,Tring S,Plummer SJ,Mendoza-Fandino GA,Hartiala J,Hitchler MJ,Yan C,Schumacher FR,Conti DV,Edlund CK,Noushmehr H,Coetzee SG,Bresalier RS,Ahnen DJ,Barry EL,Berman BP,Rice JC,Coetzee GA,Casey G

    更新日期:2014-04-15 00:00:00

  • Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease.

    abstract::Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Two susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene. Hitherto however, homozygosity for EDNRB mutation...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Amiel J,Attié T,Jan D,Pelet A,Edery P,Bidaud C,Lacombe D,Tam P,Simeoni J,Flori E,Nihoul-Fékété C,Munnich A,Lyonnet S

    更新日期:1996-03-01 00:00:00

  • Reviewing the genetics of heterogeneity in depression: operationalizations, manifestations and etiologies.

    abstract::With progress in genome-wide association studies of depression, from identifying zero hits in ~16 000 individuals in 2013 to 223 hits in more than a million individuals in 2020, understanding the genetic architecture of this debilitating condition no longer appears to be an impossible task. The pressing question now i...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Cai N,Choi KW,Fried EI

    更新日期:2020-09-30 00:00:00

  • Molecular disturbance underlies to arrhythmogenic cardiomyopathy induced by transgene content, age and exercise in a truncated PKP2 mouse model.

    abstract::Arrhythmogenic cardiomyopathy (ACM) is a disorder characterized by a progressive ventricular myocardial replacement by fat and fibrosis, which lead to ventricular arrhythmias and sudden cardiac death. Mutations in the desmosomal gene Plakophilin-2 (PKP2) accounts for >40% of all known mutations, generally causing a tr...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Moncayo-Arlandi J,Guasch E,Sanz-de la Garza M,Casado M,Garcia NA,Mont L,Sitges M,Knöll R,Buyandelger B,Campuzano O,Diez-Juan A,Brugada R

    更新日期:2016-09-01 00:00:00

  • Novel mutations in lysosomal neuraminidase identify functional domains and determine clinical severity in sialidosis.

    abstract::Lysosomal neuraminidase is the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates and is deficient in two neurodegenerative lysosomal disorders, sialidosis and galactosialidosis. Here we report the identification of eight novel mutations in the neuraminidase gene of 11 sialidosis patients with ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Bonten EJ,Arts WF,Beck M,Covanis A,Donati MA,Parini R,Zammarchi E,d'Azzo A

    更新日期:2000-11-01 00:00:00

  • Mutations and altered expression of SERPINF1 in patients with familial otosclerosis.

    abstract::Otosclerosis is a relatively common heterogenous condition, characterized by abnormal bone remodelling in the otic capsule leading to fixation of the stapedial footplate and an associated conductive hearing loss. Although familial linkage and candidate gene association studies have been performed in recent years, litt...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Ziff JL,Crompton M,Powell HR,Lavy JA,Aldren CP,Steel KP,Saeed SR,Dawson SJ

    更新日期:2016-06-15 00:00:00

  • Reproductive and epigenetic outcomes associated with aging mouse oocytes.

    abstract::Female aging entails a decline in fertility in mammals, manifested by reduced oocyte reserves and poor oocyte quality accompanied by chromosomal anomalies and reduced litter size. In addition to compromised genetic integrity, recent studies suggest that epigenetic mechanisms may be altered in aging oocytes, with age a...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Lopes FL,Fortier AL,Darricarrère N,Chan D,Arnold DR,Trasler JM

    更新日期:2009-06-01 00:00:00

  • Analysis of the human GDNF gene reveals an inducible promoter, three exons, a triplet repeat within the 3'-UTR and alternative splice products.

    abstract::Glial cell line-derived neurotrophic factor (GDNF), a distant member of the TGF-beta superfamily, is a survival factor for various neurons, making it a potential therapeutic agent for neurodegenerative disorders. Here we present the genomic structure and characterization of the promoter of the human GDNF (hGDNF) gene....

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Grimm L,Holinski-Feder E,Teodoridis J,Scheffer B,Schindelhauer D,Meitinger T,Ueffing M

    更新日期:1998-11-01 00:00:00

  • A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterol.

    abstract::Single nucleotide polymorphisms (SNPs) that alter exon splicing efficiency are an emerging class of functional genetic variants. Since mutations in low-density lipoprotein receptor (LDLR) are a primary cause of familial hypercholesterolemia, we evaluated whether LDLR SNPs may alter splicing efficiency and cholesterol ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Zhu H,Tucker HM,Grear KE,Simpson JF,Manning AK,Cupples LA,Estus S

    更新日期:2007-07-15 00:00:00

  • Molecular and cellular characterization of novel {alpha}-mannosidosis mutations.

    abstract::α-Mannosidosis is a lysosomal storage disorder caused by mutations in the MAN2B1 gene. The clinical presentation of α-mannosidosis is variable, but typically includes mental retardation, skeletal abnormalities and immune deficiency. In order to understand the molecular aetiology of α-mannosidosis, we describe here the...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Kuokkanen E,Riise Stensland HM,Smith W,Kjeldsen Buvang E,Van Nguyen L,Nilssen Ø,Heikinheimo P

    更新日期:2011-07-01 00:00:00

  • Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor epsilon subunit gene: identification and functional characterization of six new mutations.

    abstract::We describe and functionally characterize six mutations of the acetylcholine receptor (AChR) epsilon subunit gene in three congenital myasthenic syndrome patients. Endplate studies demonstrated severe endplate AChR deficiency, dispersed endplate regions and well preserved junctional folds in all three patients. Electr...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Ohno K,Quiram PA,Milone M,Wang HL,Harper MC,Pruitt JN 2nd,Brengman JM,Pao L,Fischbeck KH,Crawford TO,Sine SM,Engel AG

    更新日期:1997-05-01 00:00:00

  • Isolation and embryonic expression of the novel mouse gene Hic1, the homologue of HIC1, a candidate gene for the Miller-Dieker syndrome.

    abstract::The human gene HIC1 (hypermethylated in cancer) maps to chromosome 17p13.3 and is deleted in the contiguous gene disorder Miller-Dieker syndrome (MDS) [Makos-Wales et al. (1995) Nature Med., 1, 570-577; Chong et al. (1996) Genome Res., 6, 735-741]. We isolated the murine homologue Hic1, encoding a zinc-finger protein ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Grimm C,Spörle R,Schmid TE,Adler ID,Adamski J,Schughart K,Graw J

    更新日期:1999-04-01 00:00:00

  • Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene.

    abstract::Paroxysmal kinesigenic dyskinesia (PKD) is a heterogeneous movement disorder characterized by recurrent dyskinesia attacks triggered by sudden movement. PRRT2 has been identified as the first causative gene of PKD. However, it is only responsible for approximately half of affected individuals, indicating that other lo...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Yin XM,Lin JH,Cao L,Zhang TM,Zeng S,Zhang KL,Tian WT,Hu ZM,Li N,Wang JL,Guo JF,Wang RX,Xia K,Zhang ZH,Yin F,Peng J,Liao WP,Yi YH,Liu JY,Yang ZX,Chen Z,Mao X,Yan XX,Jiang H,Shen L,Chen SD,Zhang LM,Tan

    更新日期:2018-02-15 00:00:00

  • Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NF-kappaB signaling.

    abstract::Mutations in PTEN-induced putative kinase 1 (PINK1) or parkin cause autosomal recessive forms of Parkinson disease (PD), but how these mutations trigger neurodegeneration is poorly understood and the exact functional relationship between PINK1 and parkin remains unclear. Here, we report that PINK1 regulates the E3 ubi...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Sha D,Chin LS,Li L

    更新日期:2010-01-15 00:00:00

  • Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity.

    abstract::Huntington's disease is caused by an expanded polyglutamine tract in huntingtin protein, leading to accumulation of huntingtin in the nuclei of striatal neurons. The 18 amino-acid amino-terminus of huntingtin is an amphipathic alpha helical membrane-binding domain that can reversibly target to vesicles and the endopla...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Atwal RS,Xia J,Pinchev D,Taylor J,Epand RM,Truant R

    更新日期:2007-11-01 00:00:00

  • An evolutionarily conserved germ cell-specific hnRNP is encoded by a retrotransposed gene.

    abstract::The gene encoding heterogeneous ribonucleoprotein (hnRNP) G recently has been mapped to the X chromosome. All mammals have a Y chromosome-encoded homologue of HNRNP G called RBMY, which is implicated with a role in male fertility and is a candidate for the azoospermia factor gene. We have identified a new member of th...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Elliott DJ,Venables JP,Newton CS,Lawson D,Boyle S,Eperon IC,Cooke HJ

    更新日期:2000-09-01 00:00:00

  • The origin of the extra Y chromosome in males with a 47,XYY karyotype.

    abstract::The presence of an extra Y chromosome in males is a relatively common occurrence, the 47,XYY karyotype being found in approximately 1 in 1000 male births. The error of disjunction must occur either during paternal meiosis II or as a post-zygotic mitotic error, both of which are rare events for other chromosomes. It is...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Robinson DO,Jacobs PA

    更新日期:1999-11-01 00:00:00

  • Mouse choroideremia gene mutation causes photoreceptor cell degeneration and is not transmitted through the female germline.

    abstract::Choroideremia (CHM) is an X-linked progressive eye disorder which results from defects in the human Rab escort protein-1 (REP-1) gene. A gene targeting approach was used to disrupt the mouse chm/rep-1 gene. Chimeric males transmitted the mutated gene to their carrier daughters but, surprisingly, these heterozygous fem...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: van den Hurk JA,Hendriks W,van de Pol DJ,Oerlemans F,Jaissle G,Rüther K,Kohler K,Hartmann J,Zrenner E,van Bokhoven H,Wieringa B,Ropers HH,Cremers FP

    更新日期:1997-06-01 00:00:00

  • Systematic identification of cis-silenced genes by trans complementation.

    abstract::A gene's transcriptional output is the combined product of two inputs: diffusible factors in the cellular milieu acting in trans, and chromatin state acting in cis. Here, we describe a strategy for dissecting the relative contribution of cis versus trans mechanisms to gene regulation. Referred to as trans complementat...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Lee JH,Bugarija B,Millan EJ,Walton NM,Gaetz J,Fernandes CJ,Yu WH,Mekel-Bobrov N,Vallender TW,Snyder GE,Xiang AP,Lahn BT

    更新日期:2009-03-01 00:00:00

  • A conserved splicing mechanism of the LMNA gene controls premature aging.

    abstract::Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder phenotypically characterized by many features of premature aging. Most cases of HGPS are due to a heterozygous silent mutation (c.1824C>T; p.Gly608Gly) that enhances the use of an internal 5' splice site (5'SS) in exon 11 of the LMNA pre-mRNA and l...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Lopez-Mejia IC,Vautrot V,De Toledo M,Behm-Ansmant I,Bourgeois CF,Navarro CL,Osorio FG,Freije JM,Stévenin J,De Sandre-Giovannoli A,Lopez-Otin C,Lévy N,Branlant C,Tazi J

    更新日期:2011-12-01 00:00:00

  • Structural analysis of the minisatellite present at the 3' end of the human apolipoprotein B gene: new definition of the alleles and evolutionary implications.

    abstract::The internal structure of different alleles of the minisatellite present at the 3' end of the apolipoprotein B (ApoB) gene has been analysed by different approaches including sequencing. The repeat unit arrangements of the minisatellite on 570 chromosomes belonging to European and African populations were thus determi...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Buresi C,Desmarais E,Vigneron S,Lamarti H,Smaoui N,Cambien F,Roizes G

    更新日期:1996-01-01 00:00:00

  • Tissue-specific alternative splicing of TCF7L2.

    abstract::Common variants in the transcription factor 7-like 2 (TCF7L2) gene have been identified as the strongest genetic risk factors for type 2 diabetes (T2D). However, the mechanisms by which these non-coding variants increase risk for T2D are not well-established. We used 13 expression assays to survey mRNA expression of m...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Prokunina-Olsson L,Welch C,Hansson O,Adhikari N,Scott LJ,Usher N,Tong M,Sprau A,Swift A,Bonnycastle LL,Erdos MR,He Z,Saxena R,Harmon B,Kotova O,Hoffman EP,Altshuler D,Groop L,Boehnke M,Collins FS,Hall JL

    更新日期:2009-10-15 00:00:00