FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation.


:The recently described DNA replication-based mechanisms of fork stalling and template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR) were previously shown to catalyze complex exonic, genic and genomic rearrangements. By analyzing a large number of isochromosomes of the long arm of chromosome X (i(Xq)), using whole-genome tiling path array comparative genomic hybridization (aCGH), ultra-high resolution targeted aCGH and sequencing, we provide evidence that the FoSTeS and MMBIR mechanisms can generate large-scale gross chromosomal rearrangements leading to the deletion and duplication of entire chromosome arms, thus suggesting an important role for DNA replication-based mechanisms in both the development of genomic disorders and cancer. Furthermore, we elucidate the mechanisms of dicentric i(Xq) (idic(Xq)) formation and show that most idic(Xq) chromosomes result from non-allelic homologous recombination between palindromic low copy repeats and highly homologous palindromic LINE elements. We also show that non-recurrent-breakpoint idic(Xq) chromosomes have microhomology-associated breakpoint junctions and are likely catalyzed by microhomology-mediated replication-dependent recombination mechanisms such as FoSTeS and MMBIR. Finally, we stress the role of the proximal Xp region as a chromosomal rearrangement hotspot.


Hum Mol Genet


Human molecular genetics


Koumbaris G,Hatzisevastou-Loukidou H,Alexandrou A,Ioannides M,Christodoulou C,Fitzgerald T,Rajan D,Clayton S,Kitsiou-Tzeli S,Vermeesch JR,Skordis N,Antoniou P,Kurg A,Georgiou I,Carter NP,Patsalis PC




Has Abstract


2011-05-15 00:00:00














  • Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy.

    abstract::X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a polyglutamine (polyQ) disease in which the affected males suffer progressive motor neuron degeneration accompanied by signs of androgen insensitivity, such as gynecomastia and reduced fertility. SBMA is caused by CAG repeat expansions in the an...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Thomas PS Jr,Fraley GS,Damian V,Woodke LB,Zapata F,Sopher BL,Plymate SR,La Spada AR

    更新日期:2006-07-15 00:00:00

  • Allelic recombination and de novo deletions in sperm in the human beta-globin gene region.

    abstract::Meiotic recombination is of fundamental importance in creating haplotype diversity in the human genome and has the potential to cause genomic rearrangements by ectopic recombination between repeat sequences and through other changes triggered by recombination-initiating events. However, the relationship between alleli...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Holloway K,Lawson VE,Jeffreys AJ

    更新日期:2006-04-01 00:00:00

  • Reduction of Pax9 gene dosage in an allelic series of mouse mutants causes hypodontia and oligodontia.

    abstract::Missing teeth (hypodontia and oligodontia) are a common developmental abnormality in humans and heterozygous mutations of PAX9 have recently been shown to underlie a number of familial, non-syndromic cases. Whereas PAX9 haploinsufficiency has been suggested as the underlying genetic mechanism, it is not known how this...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Kist R,Watson M,Wang X,Cairns P,Miles C,Reid DJ,Peters H

    更新日期:2005-12-01 00:00:00

  • Junctional epidermolysis bullosa inversa (locus EBR2A) assigned to 1q31 by linkage and association to LAMC1.

    abstract::Junctional epidermolysis bullosa inversa is an autosomal recessive blistering skin disease with an ultrastructural hemidesmosome defect similar to that of the Herlitz disease, yet with a non-lethal and different course of the disease. Its delineation is based on five geographically associated Norwegian families where ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Gedde-Dahl T Jr,Dupuy BM,Jonassen R,Winberg JO,Anton-Lamprecht I,Olaisen B

    更新日期:1994-08-01 00:00:00

  • Testicular MTHFR deficiency may explain sperm DNA hypomethylation associated with high dose folic acid supplementation.

    abstract::Supplementation with high doses of folic acid, an important mediator of one-carbon transfers for DNA methylation, is used clinically to improve sperm parameters in infertile men. We recently detected an unexpected loss of DNA methylation in the sperm of idiopathic infertile men after 6 months of daily supplementation ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Aarabi M,Christensen KE,Chan D,Leclerc D,Landry M,Ly L,Rozen R,Trasler J

    更新日期:2018-04-01 00:00:00

  • Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer.

    abstract::Gene function in cancer can be disrupted either through genetic alterations, which directly mutate or delete genes, or epigenetic alterations, which alter the heritable state of gene expression. The latter events are mediated by formation of transcriptionally repressive chromatin states around gene transcription start...

    journal_title:Human molecular genetics

    pub_type: 杂志文章,评审


    authors: Baylin SB,Esteller M,Rountree MR,Bachman KE,Schuebel K,Herman JG

    更新日期:2001-04-01 00:00:00

  • TFEB activation restores migration ability to Tsc1-deficient adult neural stem/progenitor cells.

    abstract::Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major path...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Magini A,Polchi A,Di Meo D,Mariucci G,Sagini K,De Marco F,Cassano T,Giovagnoli S,Dolcetta D,Emiliani C

    更新日期:2017-09-01 00:00:00

  • A Drosophila model of GSS syndrome suggests defects in active zones are responsible for pathogenesis of GSS syndrome.

    abstract::We have established a Drosophila model of Gerstmann-Sträussler-Scheinker (GSS) syndrome by expressing mouse prion protein (PrP) having leucine substitution at residue 101 (MoPrP(P101L)). Flies expressing MoPrP(P101L), but not wild-type MoPrP (MoPrP(3F4)), showed severe defects in climbing ability and early death. Expr...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Choi JK,Jeon YC,Lee DW,Oh JM,Lee HP,Jeong BH,Carp RI,Koh YH,Kim YS

    更新日期:2010-11-15 00:00:00

  • Primary angle closure glaucoma (PACG) susceptibility gene PLEKHA7 encodes a novel Rac1/Cdc42 GAP that modulates cell migration and blood-aqueous barrier function.

    abstract::PLEKHA7, a gene recently associated with primary angle closure glaucoma (PACG), encodes an apical junctional protein expressed in components of the blood aqueous barrier (BAB). We found that PLEKHA7 is down-regulated in lens epithelial cells and in iris tissue of PACG patients. PLEKHA7 expression also correlated with ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Lee MC,Shei W,Chan AS,Chua BT,Goh SR,Chong YF,Hilmy MH,Nongpiur ME,Baskaran M,Khor CC,Aung T,Hunziker W,Vithana EN

    更新日期:2017-10-15 00:00:00

  • Translational readthrough by the aminoglycoside geneticin (G418) modulates SMN stability in vitro and improves motor function in SMA mice in vivo.

    abstract::Proximal spinal muscular atrophy (SMA) is a neuromuscular disorder for which there is no available therapy. SMA is caused by loss or mutation of the survival motor neuron 1 gene, SMN1, with retention of a nearly identical copy gene, SMN2. In contrast to SMN1, most SMN2 transcripts lack exon 7. This alternatively splic...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Heier CR,DiDonato CJ

    更新日期:2009-04-01 00:00:00

  • Allele-specific silencing of a pathogenic mutant acetylcholine receptor subunit by RNA interference.

    abstract::Slow channel congenital myasthenic syndrome (SCCMS) is a disorder of the neuromuscular synapse caused by dominantly inherited missense mutations in genes that encode the muscle acetylcholine receptor (AChR) subunits. Here we investigate the potential of post-transcriptional gene silencing using RNA interference (RNAi)...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Abdelgany A,Wood M,Beeson D

    更新日期:2003-10-15 00:00:00

  • SPEG-deficient skeletal muscles exhibit abnormal triad and defective calcium handling.

    abstract::Centronuclear myopathies (CNM) are a subtype of congenital myopathies (CM) characterized by skeletal muscle weakness and an increase in the number of central myonuclei. We have previously identified three CNM probands, two with associated dilated cardiomyopathy, carrying striated preferentially expressed gene (SPEG) m...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Huntoon V,Widrick JJ,Sanchez C,Rosen SM,Kutchukian C,Cao S,Pierson CR,Liu X,Perrella MA,Beggs AH,Jacquemond V,Agrawal PB

    更新日期:2018-05-01 00:00:00

  • Expression profiling in exercised mdx suggests a role for extracellular proteins in the dystrophic muscle immune response.

    abstract::Duchenne muscular dystrophy (DMD) is a lethal muscle wasting disorder caused by mutations in the DMD gene that leads to the absence or severe reduction of dystrophin protein in muscle. The mdx mouse, also dystrophin deficient, is the model most widely used to study the pathology and test potential therapies, but the p...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Coles CA,Gordon L,Hunt LC,Webster T,Piers AT,Kintakas C,Woodman K,Touslon SL,Smythe GM,White JD,Lamandé SR

    更新日期:2020-02-01 00:00:00

  • Two trans-acting eQTLs modulate the penetrance of PRPF31 mutations.

    abstract::Dominant mutations in the gene encoding the ubiquitously-expressed splicing factor PRPF31 cause retinitis pigmentosa, a form of hereditary retinal degeneration, with reduced penetrance. We and others have previously shown that penetrance is tightly correlated with PRPF31 expression, as lymphoblastoid cell lines (LCLs)...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Rio Frio T,Civic N,Ransijn A,Beckmann JS,Rivolta C

    更新日期:2008-10-15 00:00:00

  • Overexpression of yeast hsp104 reduces polyglutamine aggregation and prolongs survival of a transgenic mouse model of Huntington's disease.

    abstract::Huntington's disease is a devastating neurodegenerative condition associated with the formation of intraneuronal aggregates by mutant huntingtin. Aggregate formation is a property shared by the nine related diseases caused by polyglutamine codon expansion mutations and also by other neurodegenerative conditions like P...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Vacher C,Garcia-Oroz L,Rubinsztein DC

    更新日期:2005-11-15 00:00:00

  • Mutant HSPB8 causes motor neuron-specific neurite degeneration.

    abstract::Missense mutations (K141N and K141E) in the alpha-crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is curre...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Irobi J,Almeida-Souza L,Asselbergh B,De Winter V,Goethals S,Dierick I,Krishnan J,Timmermans JP,Robberecht W,De Jonghe P,Van Den Bosch L,Janssens S,Timmerman V

    更新日期:2010-08-15 00:00:00

  • An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia.

    abstract::Familial tumoral calcinosis (FTC) is an autosomal recessive disorder characterized by ectopic calcifications and elevated serum phosphate levels. Recently, mutations in the GALNT3 gene have been described to cause FTC. The FTC phenotype is regarded as the metabolic mirror image of hypophosphatemic conditions, where ca...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Benet-Pagès A,Orlik P,Strom TM,Lorenz-Depiereux B

    更新日期:2005-02-01 00:00:00

  • Up-regulation of c-Jun N-terminal kinase pathway in Friedreich's ataxia cells.

    abstract::The severe reduction in mRNA and protein levels of the mitochondrial protein frataxin, encoded by the X25 gene, causes Friedreich ataxia (FRDA), the most common form of recessive hereditary ataxia. Increasing evidence underlines the pathogenetic role of oxidative stress in this disease. We generated an in vitro cellul...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Pianese L,Busino L,De Biase I,De Cristofaro T,Lo Casale MS,Giuliano P,Monticelli A,Turano M,Criscuolo C,Filla A,Varrone S,Cocozza S

    更新日期:2002-11-01 00:00:00

  • Frequent deletion of chromosome 1p sequences in an aggressive histologic subtype of endometrial cancer.

    abstract::The molecular genetic events underlying endometrial tumorigenesis are ill-defined at present. We have identified a region on the short arm of chromosome 1 which is frequently deleted in endometrial cancers. The region of deletion has been localized to bands 1p32-33. Deletion of 1p32-33 is seen more frequently in cance...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Arlt MF,Herzog TJ,Mutch DG,Gersell DJ,Liu H,Goodfellow PJ

    更新日期:1996-07-01 00:00:00

  • Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis.

    abstract::Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Although the mutant protein is widely expressed, the earliest and most striking neuropathological changes are observed in the striatum. Here we show dramatic mutation length increases (gai...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Kennedy L,Evans E,Chen CM,Craven L,Detloff PJ,Ennis M,Shelbourne PF

    更新日期:2003-12-15 00:00:00

  • Loss of Tbx1 induces bone phenotypes similar to cleidocranial dysplasia.

    abstract::T-box transcription factor, TBX1, is the major candidate gene for 22q11.2 deletion syndrome (DiGeorge/ Velo-cardio-facial syndrome) characterized by facial defects, thymus hypoplasia, cardiovascular anomalies and cleft palates. Here, we report that the loss of Tbx1 in mouse (Tbx1(-/-)) results in skeletal abnormalitie...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Funato N,Nakamura M,Richardson JA,Srivastava D,Yanagisawa H

    更新日期:2015-01-15 00:00:00

  • Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis.

    abstract::Microsatellite instability (MSI) characterizes tumors arising in patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome. HNPCC is a hereditary autosomal dominant disease caused by germline mutations in genes from the DNA (MMR) mismatch repair system. In these tumors, the loss of MMR compromises the ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Alazzouzi H,Domingo E,González S,Blanco I,Armengol M,Espín E,Plaja A,Schwartz S,Capella G,Schwartz S Jr

    更新日期:2005-01-15 00:00:00

  • Involvement of multiple developmental genes on chromosome 1p in lung tumorigenesis.

    abstract::Lung cancer is the leading cause of cancer death in North America. Despite advances in lung cancer treatment, the overall 5 year survival rate for those diagnosed with the disease is bleak presumably due to the late stage of diagnosis. Owing to the difficulty of early detection, preneoplastic specimens are rare. Howev...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Garnis C,Campbell J,Davies JJ,Macaulay C,Lam S,Lam WL

    更新日期:2005-02-15 00:00:00

  • A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration.

    abstract::Inherited retinal dystrophies are a group of genetically heterogeneous conditions with broad phenotypic heterogeneity. We analyzed a large five-generation pedigree with early-onset recessive retinal degeneration to identify the causative mutation. Linkage analysis and homozygosity mapping combined with exome sequencin...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Biswas P,Chavali VR,Agnello G,Stone E,Chakarova C,Duncan JL,Kannabiran C,Homsher M,Bhattacharya SS,Naeem MA,Kimchi A,Sharon D,Iwata T,Riazuddin S,Reddy GB,Hejtmancik JF,Georgiou G,Riazuddin SA,Ayyagari R

    更新日期:2016-06-15 00:00:00

  • Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene.

    abstract::The mutation causing myotonic dystrophy (DM) has recently been identified as an unstable CTG trinucleotide repeat located in the 3' untranslated region of a gene encoding for a protein with putative serine-threonine protein kinase activity. In this report we present the genomic sequences of the human and murine DM kin...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Mahadevan MS,Amemiya C,Jansen G,Sabourin L,Baird S,Neville CE,Wormskamp N,Segers B,Batzer M,Lamerdin J

    更新日期:1993-03-01 00:00:00

  • Construction of a YAC contig and a STS map spanning at least seven megabasepairs in chromosome 5q34-35.

    abstract::We have constructed a YAC contig containing 54 clones and a minimum of 7 Mbp of human DNA, that maps to bands q34-35 on chromosome 5. The contig was nucleated using FISH mapped cosmid clones shown to flank the t(2;5)(p23;q35) translocation breakpoint in a CD30-positive large cell lymphoma cell line. Thirty of the 54 Y...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Lu-Kuo JM,Le Paslier D,Weissenbach J,Chumakov I,Cohen D,Ward DC

    更新日期:1994-01-01 00:00:00

  • Functional characterization of SIM1-associated enhancers.

    abstract::Haploinsufficiency of the single-minded homology 1 (SIM1) gene in humans and mice leads to severe obesity, suggesting that altered expression of SIM1, by way of regulatory elements such as enhancers, could predispose individuals to obesity. Here, we identified transcriptional enhancers that could regulate SIM1, using ...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Kim MJ,Oksenberg N,Hoffmann TJ,Vaisse C,Ahituv N

    更新日期:2014-04-01 00:00:00

  • Evolutionary redesign of the lysosomal enzyme arylsulfatase A increases efficacy of enzyme replacement therapy for metachromatic leukodystrophy.

    abstract::Protein engineering is a means to optimize protein therapeutics developed for the treatment of so far incurable diseases including cancers and genetic disorders. Here we report on an engineering approach in which we successfully increased the catalytic rate constant of an enzyme that is presently evaluated in enzyme r...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Simonis H,Yaghootfam C,Sylvester M,Gieselmann V,Matzner U

    更新日期:2019-06-01 00:00:00

  • The limb-girdle muscular dystrophies-multiple genes, multiple mechanisms.

    abstract::In the field of muscular dystrophy, advances in understanding the molecular basis of the various disorders in this group have been rapidly translated into readily applicable diagnostic tests, allowing the provision of more accurate prognostic and genetic counselling. The limb-girdle muscular dystrophies (LGMD) have re...

    journal_title:Human molecular genetics

    pub_type: 杂志文章,评审


    authors: Bushby KM

    更新日期:1999-01-01 00:00:00

  • Variegated yet non-random rod and cone photoreceptor disease patterns in RPGR-ORF15-associated retinal degeneration.

    abstract::Mutations in the ORF15 exon of the RPGR gene cause a common form of X-linked retinitis pigmentosa, which often results in severe loss of vision. In dogs and mice, gene augmentation therapy has been shown to arrest the progressive degeneration of rod and cone photoreceptors. However, the distribution of potentially tre...

    journal_title:Human molecular genetics

    pub_type: 杂志文章


    authors: Charng J,Cideciyan AV,Jacobson SG,Sumaroka A,Schwartz SB,Swider M,Roman AJ,Sheplock R,Anand M,Peden MC,Khanna H,Heon E,Wright AF,Swaroop A

    更新日期:2016-12-15 00:00:00