A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N).


:Charcot-Marie-Tooth (CMT) disease comprises a heterogeneous group of peripheral neuropathies characterized by muscle weakness and wasting, and impaired sensation in the extremities. Four genes encoding an aminoacyl-tRNA synthetase (ARS) have been implicated in CMT disease. ARSs are ubiquitously expressed, essential enzymes that ligate amino acids to cognate tRNA molecules. Recently, a p.Arg329His variant in the alanyl-tRNA synthetase (AARS) gene was found to segregate with dominant axonal CMT type 2N (CMT2N) in two French families; however, the functional consequence of this mutation has not been determined. To investigate the role of AARS in CMT, we performed a mutation screen of the AARS gene in patients with peripheral neuropathy. Our results showed that p.Arg329His AARS also segregated with CMT disease in a large Australian family. Aminoacylation and yeast viability assays showed that p.Arg329His AARS severely reduces enzyme activity. Genotyping analysis indicated that this mutation arose on three distinct haplotypes, and the results of bisulfite sequencing suggested that methylation-mediated deamination of a CpG dinucleotide gives rise to the recurrent p.Arg329His AARS mutation. Together, our data suggest that impaired tRNA charging plays a role in the molecular pathology of CMT2N, and that patients with CMT should be directly tested for the p.Arg329His AARS mutation.


Hum Mutat


Human mutation


McLaughlin HM,Sakaguchi R,Giblin W,NISC Comparative Sequencing Program.,Wilson TE,Biesecker L,Lupski JR,Talbot K,Vance JM,Züchner S,Lee YC,Kennerson M,Hou YM,Nicholson G,Antonellis A




Has Abstract


2012-01-01 00:00:00












  • Mutational analysis of the HGSNAT gene in Italian patients with mucopolysaccharidosis IIIC (Sanfilippo C syndrome). Mutation in brief #959. Online.

    abstract::Mucopolysaccharidosis (MPS) describes any inherited lysosomal storage disorder resulting from an inability to catabolize glycosaminoglycans. MPS III (or Sanfilippo syndrome) is an autosomal recessive disease caused by a failure to degrade heparan sulphate. There are four subtypes of MPS III, each categorized by a defi...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Fedele AO,Filocamo M,Di Rocco M,Sersale G,Lübke T,di Natale P,Cosma MP,Ballabio A

    更新日期:2007-05-01 00:00:00

  • Determination of 30 X-linked adrenoleukodystrophy mutations, including 15 not previously described.

    abstract::X-linked Adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease. It mainly involves the nervous system white matter, adrenal cortex and testes. Several distinct clinical phenotypes are known. The principal biochemical abnormality is the accumulation of saturated very-long-chain fatty acids (VLCFAs : > C...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lachtermacher MB,Seuánez HN,Moser AB,Moser HW,Smith KD

    更新日期:2000-01-01 00:00:00

  • Novel mutations in African American patients with glycogen storage disease Type II. Mutations in brief no. 209. Online.

    abstract::The infantile form of GSD II (an inherited deficiency of the lysosomal enzyme, acid alpha-glucosidase, Pompe disease) is a severe and invariably fatal disease characterized by a rapidly progressive generalized hypotonia, hepatomegaly, and cardiomegaly. We have recently demonstrated that African American patients share...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Raben N,Lee E,Lee L,Hirschhorn R,Plotz PH

    更新日期:1999-01-01 00:00:00

  • IL-12Rβ1 deficiency: mutation update and description of the IL12RB1 variation database.

    abstract::IL-12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and salmonella. IL-12Rβ1 is a receptor chain of both the IL-12 and the IL-23 receptor and deficiency of IL-12Rβ1 thus abolishes both IL-12 and ...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: van de Vosse E,Haverkamp MH,Ramirez-Alejo N,Martinez-Gallo M,Blancas-Galicia L,Metin A,Garty BZ,Sun-Tan Ç,Broides A,de Paus RA,Keskin Ö,Çağdaş D,Tezcan I,Lopez-Ruzafa E,Aróstegui JI,Levy J,Espinosa-Rosales FJ,Sanal Ö,

    更新日期:2013-10-01 00:00:00

  • Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease.

    abstract::Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by m...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Schmidts M,Frank V,Eisenberger T,Al Turki S,Bizet AA,Antony D,Rix S,Decker C,Bachmann N,Bald M,Vinke T,Toenshoff B,Di Donato N,Neuhann T,Hartley JL,Maher ER,Bogdanović R,Peco-Antić A,Mache C,Hurles ME,Joksić I,G

    更新日期:2013-05-01 00:00:00

  • Usher syndrome type 1 due to missense mutations on both CDH23 alleles: investigation of mRNA splicing.

    abstract::Usher syndrome (USH) is an autosomal recessive condition characterized by sensorineural hearing loss, vestibular dysfunction, and visual impairment due to retinitis pigmentosa. Truncating mutations in the cadherin-23 gene (CDH23) result in Usher syndrome type 1D (USH1D), whereas missense mutations affecting strongly c...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Becirovic E,Ebermann I,Nagy D,Zrenner E,Seeliger MW,Bolz HJ

    更新日期:2008-03-01 00:00:00

  • A single, large deletion accounts for all the beta-globin gene mutations in twenty families from Sabah (North Borneo), Malaysia. Mutation in brief no. 240. Online.

    abstract::Beta-thalassemia major is one of the commonest genetic disorders in South-East Asia. The spectrum of beta-thalassemia mutations in the various ethnic sub-populations on the island of Borneo is unknown. We studied 20 Dusun children from the East Malaysian state of Sabah (North Borneo) with a severe beta-thalassemia maj...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Thong MK,Rudzki Z,Hall J,Tan JA,Chan LL,Yap SF

    更新日期:1999-01-01 00:00:00

  • Transthyretin mutations in health and disease.

    abstract::To date, over 40 different mutations in transthyretin (TTR) have been associated with amyloid deposition. The major unresolved problem is the correlation between the clinical heterogeneity and the genetic heterogeneity. For instance, whereas some mutations produce neuropathy and some give rise to cardiomyopathy, other...

    journal_title:Human mutation

    pub_type: 杂志文章,评审


    authors: Saraiva MJ

    更新日期:1995-01-01 00:00:00

  • Mutation detection in the duplicated region of the polycystic kidney disease 1 (PKD1) gene in PKD1-linked Australian families.

    abstract::Screening for disease-causing mutations in the duplicated region of the PKD1 gene was performed in 17 unrelated Australian individuals with PKD1-linked autosomal dominant polycystic kidney disease. Exons 2-21 and 23-34 were assayed using PKD1-specific PCR amplification and direct sequencing. We have identified 12 nove...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: McCluskey M,Schiavello T,Hunter M,Hantke J,Angelicheva D,Bogdanova N,Markoff A,Thomas M,Dworniczak B,Horst J,Kalaydjieva L

    更新日期:2002-03-01 00:00:00

  • A large deletion mutation in the CFTR gene (3120+1Kbdel8.6Kb): a founder mutation in the Palestinian Arabs. Mutation in brief no. 231. Online.

    abstract::A deletion mutation of 8.6Kb in the CFTR gene, spanning the exons 17a, 17b and 18 was identified in 4 homozygous unrelated Palestinian CF patients. The patients were of various ethnic subgroups including Muslims, Christians and Druze. The deletion breakpoint occurred within an identical 4bp sequence in introns 16 and ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lerer I,Laufer-Cahana A,Rivlin JR,Augarten A,Abeliovich D

    更新日期:1999-01-01 00:00:00

  • Ataxia-telangiectasia in the Japanese population: identification of R1917X, W2491R, R2909G, IVS33+2T-->A, and 7883del5, the latter two being relatively common mutations.

    abstract::We analyzed the data regarding six Japanese ataxia-telangiectasia (A-T) patients from four unrelated families, at the DNA level, to search for possible common mutations in the Japanese population. Among eight mutant alleles in the four families, c. 4612del165 (exon 33 skipping) was identified in two alleles, and c. 57...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Fukao T,Song XQ,Yoshida T,Tashita H,Kaneko H,Teramoto T,Inoue R,Katamura K,Mayumi M,Hiratani M,Taniguchi N,Arai J,Wakiguchi H,Bar-Shira A,Shiloh Y,Kondo N

    更新日期:1998-01-01 00:00:00

  • D-glyceric aciduria is caused by genetic deficiency of D-glycerate kinase (GLYCTK).

    abstract::D-glyceric aciduria is a rare inborn error of serine and fructose metabolism that was first described in 1974. Most affected individuals have presented with neurological symptoms. The molecular basis of D-glyceric aciduria is largely unknown; possible causes that have been discussed are deficiencies of D-glycerate deh...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Sass JO,Fischer K,Wang R,Christensen E,Scholl-Bürgi S,Chang R,Kapelari K,Walter M

    更新日期:2010-12-01 00:00:00

  • Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.

    abstract::Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Meester JAN,Sukalo M,Schröder KC,Schanze D,Baynam G,Borck G,Bramswig NC,Duman D,Gilbert-Dussardier B,Holder-Espinasse M,Itin P,Johnson DS,Joss S,Koillinen H,McKenzie F,Morton J,Nelle H,Reardon W,Roll C,Salih MA,Sa

    更新日期:2018-09-01 00:00:00

  • Cytogenetically visible inversions are formed by multiple molecular mechanisms.

    abstract::Cytogenetically detected inversions are generally assumed to be copy number and phenotypically neutral events. While nonallelic homologous recombination is thought to play a major role, recent data suggest the involvement of other molecular mechanisms in inversion formation. Using a combination of short-read whole-gen...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pettersson M,Grochowski CM,Wincent J,Eisfeldt J,Breman AM,Cheung SW,Krepischi ACV,Rosenberg C,Lupski JR,Ottosson J,Lovmar L,Gacic J,Lundberg ES,Nilsson D,Carvalho CMB,Lindstrand A

    更新日期:2020-11-01 00:00:00

  • Dilated cardiomyopathy-associated BAG3 mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes.

    abstract::Dilated cardiomyopathy (DCM) is characterized by dilation of left ventricular cavity with systolic dysfunction. Clinical symptom of DCM is heart failure, often associated with cardiac sudden death. About 20-35% of DCM patients have apparent family histories and it has been revealed that mutations in genes for sarcomer...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Arimura T,Ishikawa T,Nunoda S,Kawai S,Kimura A

    更新日期:2011-12-01 00:00:00

  • Five novel mutations in the lysosomal sialidase gene (NEU1) in type II sialidosis patients and assessment of their impact on enzyme activity and intracellular targeting using adenovirus-mediated expression.

    abstract::Sialidosis is an autosomal recessive disease resulting from a deficiency of lysosomal sialidase. Type II sialidosis is a rare disease characterized clinically by hydrops fetalis, hepatosplenomegaly, and severe psychomotor retardation. Genomic DNA from four unrelated sialidosis patients was screened for mutations withi...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Pattison S,Pankarican M,Rupar CA,Graham FL,Igdoura SA

    更新日期:2004-01-01 00:00:00

  • Novel TSC2 mutations and decreased expression of tuberin in cultured tumor cells with an insertion mutation.

    abstract::Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in many organs. Two genes responsible for TSC, TSC1 and TSC2, were recently identified. TSC1 and TSC2 encode the proteins hamartin and tuberin, respectively, and 337 different mutations have been reported in these genes thus...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Feng JH,Yamamoto T,Nanba E,Ninomiya H,Oka A,Ohno K

    更新日期:2004-04-01 00:00:00

  • Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency.

    abstract::Primary systemic carnitine deficiency (SCD) is an autosomal recessive disorder of fatty acid oxidation caused by defective cellular carnitine transport. The disease is characterized by metabolic derangement simulating Reye's syndrome, hypoglcaemia, progressive cardiomyopathy and skeletal myopathy. Recently, it was sho...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Mayatepek E,Nezu J,Tamai I,Oku A,Katsura M,Shimane M,Tsuji A

    更新日期:2000-01-01 00:00:00

  • High-resolution breakpoint analysis provides evidence for the sequence-directed nature of genome rearrangements in hereditary disorders.

    abstract::Although most of the pertinent data on the sequence-directed processes leading to genome rearrangements (GRs) have come from studies on somatic tissues, little is known about GRs in the germ line of patients with hereditary disorders. This study aims at identifying DNA motifs and higher order structures of genome arch...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Kovac MB,Kovacova M,Bachraty H,Bachrata K,Piscuoglio S,Hutter P,Ilencikova D,Bartosova Z,Tomlinson I,Roethlisberger B,Heinimann K

    更新日期:2015-02-01 00:00:00

  • Congenital myasthenic syndrome due to mutations in MUSK suggests that the level of MuSK phosphorylation is crucial for governing synaptic structure.

    abstract::MUSK encodes the muscle-specific receptor tyrosine kinase (MuSK), a key component of the agrin-LRP4-MuSK-DOK7 signaling pathway, which is essential for the formation and maintenance of highly specialized synapses between motor neurons and muscle fibers. We report a patient with severe early-onset congenital myasthenic...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Rodríguez Cruz PM,Cossins J,Cheung J,Maxwell S,Jayawant S,Herbst R,Waithe D,Kornev AP,Palace J,Beeson D

    更新日期:2020-03-01 00:00:00

  • Overexpression of the C-type natriuretic peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced t(2;7) translocation.

    abstract::Longitudinal bone growth is determined by the process of endochondral ossification in the cartilaginous growth plate, which is located at both ends of vertebrae and long bones and involves many systemic hormones and local regulators. We report the molecular characterization of a de novo balanced t(2;7)(q37.1;q21.3) tr...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Bocciardi R,Giorda R,Buttgereit J,Gimelli S,Divizia MT,Beri S,Garofalo S,Tavella S,Lerone M,Zuffardi O,Bader M,Ravazzolo R,Gimelli G

    更新日期:2007-07-01 00:00:00

  • Determination of haplotypes from single DNA molecules: a method for single-molecule barcoding.

    abstract::Determining the haplotypes in a diploid individual is a major technical challenge in genetic studies of human complex traits. Here we report a method of molecular haplotyping by directly imaging multiple polymorphic sites on individual DNA molecules simultaneously. DNA fragments amplified by long-range PCR were labele...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Xiao M,Gordon MP,Phong A,Ha C,Chan TF,Cai D,Selvin PR,Kwok PY

    更新日期:2007-09-01 00:00:00

  • Characterization of seven novel mutations in seven patients with GAMT deficiency.

    abstract::Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive error of creatine synthesis characterized by cerebral creatine deficiency, accumulation of guanidinoacetate, mental retardation, epilepsy and extrapyramidal signs. So far, six mutations have been identified in seven patients. We investigate...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Item CB,Mercimek-Mahmutoglu S,Battini R,Edlinger-Horvat C,Stromberger C,Bodamer O,Mühl A,Vilaseca MA,Korall H,Stöckler-Ipsiroglu S

    更新日期:2004-05-01 00:00:00

  • CACNA1H variants are not a cause of monogenic epilepsy.

    abstract::CACNA1H genetic variants were originally reported in a childhood absence epilepsy cohort. Subsequently, genetic testing for CACNA1H became available and is currently offered by commercial laboratories. However, the current status of CACNA1H as a monogenic cause of epilepsy is controversial, highlighted by ClinGen's re...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Calhoun JD,Huffman AM,Bellinski I,Kinsley L,Bachman E,Gerard E,Kearney JA,Carvill GL

    更新日期:2020-06-01 00:00:00

  • Mucolipidosis II-related mutations inhibit the exit from the endoplasmic reticulum and proteolytic cleavage of GlcNAc-1-phosphotransferase precursor protein (GNPTAB).

    abstract::Mucolipidosis (ML) II and MLIII alpha/beta are two pediatric lysosomal storage disorders caused by mutations in the GNPTAB gene, which encodes an α/β-subunit precursor protein of GlcNAc-1-phosphotransferase. Considerable variations in the onset and severity of the clinical phenotype in these diseases are observed. We ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: De Pace R,Coutinho MF,Koch-Nolte F,Haag F,Prata MJ,Alves S,Braulke T,Pohl S

    更新日期:2014-03-01 00:00:00

  • A novel mutation in AlphaA-crystallin (CRYAA) caused autosomal dominant congenital cataract in a large Chinese family.

    abstract::Hereditary cataract is a phenotypically and genetically heterogeneous lens disease that is responsible for a significant proportion of the visual impairment and blindness that occurs in children. In a five-generation Chinese family with autosomal dominant inherited congenital cataract, clinical examination showed thre...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Gu F,Luo W,Li X,Wang Z,Lu S,Zhang M,Zhao B,Zhu S,Feng S,Yan YB,Huang S,Ma X

    更新日期:2008-05-01 00:00:00

  • Somatic expansion in mouse and human carriers of fragile X premutation alleles.

    abstract::Repeat expansion diseases result from expansion of a specific tandem repeat. The three fragile X-related disorders (FXDs) arise from germline expansions of a CGG•CCG repeat tract in the 5' UTR (untranslated region) of the fragile X mental retardation 1 (FMR1) gene. We show here that in addition to germline expansion, ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Lokanga RA,Entezam A,Kumari D,Yudkin D,Qin M,Smith CB,Usdin K

    更新日期:2013-01-01 00:00:00

  • A functional assay to classify ZBTB24 missense variants of unknown significance.

    abstract::Increasing use of next-generation sequencing technologies in clinical diagnostics allows large-scale discovery of genetic variants, but also results in frequent identification of variants of unknown significance (VUSs). Their classification into disease-causing and neutral variants is often hampered by the absence of ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Wu H,Vonk KKD,van der Maarel SM,Santen GWE,Daxinger L

    更新日期:2019-08-01 00:00:00

  • The molecular basis of X-linked deafness type 3 (DFN3) in two sporadic cases: identification of a somatic mosaicism for a POU3F4 missense mutation.

    abstract::We have investigated two unrelated males with X-linked deafness type 3 (DFN3) for mutations in the POU3F4 gene. In one patient, we observed a mutation that is predicted to result in an Arg330Ser amino acid substitution. In another DFN3 patient, a somatic mosaicism for an Arg323Gly amino acid substitution was found. Th...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: de Kok YJ,Cremers CW,Ropers HH,Cremers FP

    更新日期:1997-01-01 00:00:00

  • VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans.

    abstract::Vax1 and Vax2 have been implicated in eye development and the closure of the choroid fissure in mice and zebrafish. We sequenced the coding exons of VAX1 and VAX2 in 70 patients with anophthalmia/microphthalmia (A/M). In VAX1, we observed homozygosity for two successive nucleotide substitutions c.453G>A and c.454C>A, ...

    journal_title:Human mutation

    pub_type: 杂志文章


    authors: Slavotinek AM,Chao R,Vacik T,Yahyavi M,Abouzeid H,Bardakjian T,Schneider A,Shaw G,Sherr EH,Lemke G,Youssef M,Schorderet DF

    更新日期:2012-02-01 00:00:00