Abstract:
:The integrity and dynamic properties of the microtubule cytoskeleton are indispensable for the development of the mammalian brain. Consequently, mutations in the genes that encode the structural component (the α/β-tubulin heterodimer) can give rise to severe, sporadic neurodevelopmental disorders. These are commonly referred to as the tubulinopathies. Here we report the addition of recessive quadrupedalism, also known as Uner Tan syndrome (UTS), to the growing list of diseases caused by tubulin variants. Analysis of a consanguineous UTS family identified a biallelic TUBB2B mutation, resulting in a p.R390Q amino acid substitution. In addition to the identifying quadrupedal locomotion, all three patients showed severe cerebellar hypoplasia. None, however, displayed the basal ganglia malformations typically associated with TUBB2B mutations. Functional analysis of the R390Q substitution revealed that it did not affect the ability of β-tubulin to fold or become assembled into the α/β-heterodimer, nor did it influence the incorporation of mutant-containing heterodimers into microtubule polymers. The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal conditions, but did result in increased sensitivity to microtubule-depolymerizing drugs, indicative of a mild impact of this mutation on microtubule function. The TUBB2B mutation described here represents an unusual recessive mode of inheritance for missense-mediated tubulinopathies and reinforces the sensitivity of the developing cerebellum to microtubule defects.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Breuss MW,Nguyen T,Srivatsan A,Leca I,Tian G,Fritz T,Hansen AH,Musaev D,McEvoy-Venneri J,James KN,Rosti RO,Scott E,Tan U,Kolodner RD,Cowan NJ,Keays DA,Gleeson JGdoi
10.1093/hmg/ddw383subject
Has Abstractpub_date
2017-01-15 00:00:00pages
258-269issue
2eissn
0964-6906issn
1460-2083pii
ddw383journal_volume
26pub_type
杂志文章abstract::According to the telomere hypothesis of senescence, the progressive shortening of telomeres that occurs upon division of normal somatic cells eventually leads to cellular senescence. The immortalisation of human cells is associated with the acquisition of a telomere maintenance mechanism which is usually dependent upo...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.6.921
更新日期:1997-06-01 00:00:00
abstract::A 1.5 Mb duplication within 17p11.2 is the major mutation causing both autosomal dominant and sporadic Charcot-Marie-Tooth disease type 1A (CMT1A). An independent origin for the mutation in each family has been postulated. The proposed genetic mechanism causing the CMT1A duplication is unequal nonsister chromatid exch...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.12.2031
更新日期:1993-12-01 00:00:00
abstract::Long non-coding RNAs (lncRNAs) are post-transcriptional and epigenetic regulators, whose implication in neurodegenerative and autoimmune diseases remains poorly understood. We analyzed publicly available microarray data sets to identify dysregulated lncRNAs in multiple sclerosis (MS), a neuroinflammatory autoimmune di...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy438
更新日期:2019-05-01 00:00:00
abstract::We present the analysis of a prospective multicentre study to investigate genetic effects on the prognosis of newly treated epilepsy. Patients with a new clinical diagnosis of epilepsy requiring medication were recruited and followed up prospectively. The clinical outcome was defined as freedom from seizures for a min...
journal_title:Human molecular genetics
pub_type: 杂志文章,多中心研究
doi:10.1093/hmg/ddt403
更新日期:2014-01-01 00:00:00
abstract::Protein translation is an essential cellular process initiated by the association of a methionyl-tRNA with the translation initiation factor eIF2. The Met-tRNA/eIF2 complex then associates with the small ribosomal subunit, other translation factors and mRNA, which together comprise the translational initiation complex...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv337
更新日期:2015-11-15 00:00:00
abstract::We have constructed a long-range restriction map of the region on chromosome 4q that contains the gene for facioscapulohumeral muscular dystrophy (FSHD). This region contains the linkage group cen ... D4S163-D4S139-D4F35S1-D4F104S1-FSHD ... 4qter, which spans a genetic distance of about 5 cM. Pulse field gel electroph...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/2.10.1667
更新日期:1993-10-01 00:00:00
abstract::CUL4A and CUL4B are closely related cullin family members and can each assemble a Cullin-RING E3 ligase complex (CRL) and participate in a variety of biological processes. While the CRLs formed by the two cullin members may have common targets, the two appeared to have very different consequences when mutated or disru...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddu503
更新日期:2015-02-01 00:00:00
abstract::Understanding the role of the epigenome in protein-misfolding diseases remains a challenge in light of genetic diversity found in the world-wide population revealed by human genome sequencing efforts and the highly variable response of the disease population to therapeutics. An ever-growing body of evidence has shown ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz026
更新日期:2019-06-15 00:00:00
abstract::Expansion of a polyglutamine tract in ataxin-3 (AT3) results in spinocerebellar ataxia type 3/Machado-Joseph disease, one of the nine polyglutamine neurodegenerative diseases. Understanding the normal functions of AT3 as well as its function in the context of expansion of the polyglutamine tract is critical for unders...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl164
更新日期:2006-08-15 00:00:00
abstract::Pre-B cell leukemia factor 1 (PBX1) is an essential developmental transcription factor, mutations in which have recently been associated with CAKUTHED syndrome, characterized by multiple congenital defects including congenital heart disease (CHD). During analysis of a whole-exome-sequenced cohort of heterogeneous CHD ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz231
更新日期:2020-05-08 00:00:00
abstract::Mutations in PKD1 cause dominant polycystic kidney disease (PKD), characterized by large fluid-filled kidney cysts in adult life, but the molecular mechanism of cystogenesis remains obscure. Ostrom et al. [Dev. Biol., 219, 250-258 (2000)] showed that reduced dosage of Pax2 caused increased apoptosis, and ameliorated c...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl428
更新日期:2006-12-15 00:00:00
abstract::Pseudoachondroplasia (PSACH) is one of the more common skeletal dysplasias and results from mutations in cartilage oligomeric matrix protein (COMP). Most COMP mutations identified to date cluster in the TSP3 repeat region of COMP and the mutant protein is retained in the rough endoplasmic reticulum (rER) of chondrocyt...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm155
更新日期:2007-09-01 00:00:00
abstract::Deficiency of thymidine kinase 2 (TK2) is a frequent cause of isolated myopathy or encephalomyopathy in children with mitochondrial DNA (mtDNA) depletion. To determine the bases of disease onset, organ specificity and severity of TK2 deficiency, we have carefully characterized Tk2 H126N knockin mice (Tk2-/-). Although...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq453
更新日期:2011-01-01 00:00:00
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
doi:10.1093/hmg/10.7.687
更新日期:2001-04-01 00:00:00
abstract::Genome-wide association studies (GWAS) have identified several common loci contributing to non-obstructive azoospermia (NOA). However, a substantial fraction of NOA heritability remains undefined, especially those low-frequency [defined here as having a minor allele frequency (MAF) between 0.5 and 5%] and rare (MAF be...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv257
更新日期:2015-10-01 00:00:00
abstract::In a forward genetic screen in Drosophila melanogaster, aimed to identify genes required for normal locomotor function, we isolated dPPCS (the second enzyme of the Coenzyme A biosynthesis pathway). The entire Drosophila CoA synthesis route was dissected, annotated and additional CoA mutants were obtained (dPANK/fumble...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn105
更新日期:2008-07-01 00:00:00
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
doi:10.1093/hmg/ddp500
更新日期:2010-01-15 00:00:00
abstract::Southern blot analysis of the COL4A5 gene in a 6 year old Italian Alport patient (proband VIZ) showed the loss of an MspI site that was present in the mother and control DNAs. PCR amplification and DNA sequencing revealed a single G-->A nucleotide change. The mutation results in substitution of a glutamic acid for a g...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/1.2.127
更新日期:1992-05-01 00:00:00
abstract::A long-standing question concerning X-chromosome inactivation (XCI) has been how some genes avoid the otherwise stable chromosome-wide heterochromatinization of the inactive X chromosome. As 20% or more of human X-linked genes escape from inactivation, such genes are an important contributor to sex differences in gene...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddy039
更新日期:2018-04-01 00:00:00
abstract::Alternative splicing emerges as one of the most important mechanisms to generate transcript diversity. It is regulated by the formation of protein complexes on pre-mRNA. We demonstrate that protein phosphatase 1 (PP1) binds to the splicing factor transformer2-beta1 (tra2-beta1) via a phylogenetically conserved RVDF se...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddm284
更新日期:2008-01-01 00:00:00
abstract::The role of BRCA1 in breast and ovarian tumor suppression has been primarily ascribed to the maintenance of genome integrity. BRCA1 interacts with components of the non-homologous end-joining pathway previously shown to play a role in telomere maintenance in yeast. Here, we provide evidence that links Brca1 with telom...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddl002
更新日期:2006-03-15 00:00:00
abstract::Genetics of Holoprosencephaly (HPE), a congenital malformation of the developing human forebrain, is due to multiple genetic defects. Most genes that have been implicated in HPE belong to the sonic hedgehog signaling pathway. Here we describe a new candidate gene isolated from array comparative genomic hybridization r...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq556
更新日期:2011-03-15 00:00:00
abstract::The fields of both developmental and stem cell biology explore how functionally distinct cell types arise from a self-renewing founder population. Multipotent, proliferative human neural crest cells (hNCC) develop toward the end of the first month of pregnancy. It is assumed that most differentiate after migrating thr...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn235
更新日期:2008-11-01 00:00:00
abstract::Dysregulation of Fused in Sarcoma (FUS) gene expression is associated with fronto-temporal lobar degeneration (FTLD), and missense mutations in the FUS gene have been identified in patients affected by amyotrophic lateral sclerosis (ALS). However, molecular and cellular defects underlying FUS proteinopathy remain to b...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddw310
更新日期:2016-12-01 00:00:00
abstract::Recent genome-wide association studies (GWAS) have revealed genetic risk factors in autoimmune and inflammatory disorders. Several of the associated genes and underlying pathways are shared by various autoimmune diseases. Rheumatoid arthritis (RA) and coeliac disease (CD) are two autoimmune disorders which have common...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp365
更新日期:2009-11-01 00:00:00
abstract::The transient receptor potential vanilloid 1 (TRPV1) protein is a pain receptor that elicits a hot sensation when an organism eats the capsaicin of red chili peppers. This calcium (Ca2+)-permeable cation channel is mostly expressed in the peripheral nervous system sensory neurons but also in the central nervous system...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddz276
更新日期:2020-01-15 00:00:00
abstract::Protein-protein interactions are fundamental to all biological processes, and a comprehensive determination of all protein-protein interactions that can take place in an organism provides a framework for understanding biology as an integrated system. The availability of genome-scale sets of cloned open reading frames ...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddi335
更新日期:2005-10-15 00:00:00
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
doi:10.1093/hmg/ddi034
更新日期:2005-02-01 00:00:00
abstract::RAD51C was defined by Meindl et al. in 2010 as a high-risk gene involved in hereditary breast and ovarian cancers. Although this role seems to be clear, nowadays there is controversy about the indication of including the gene in routine clinical genetic testing, due to the lower prevalence or the absence of mutations ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/dds115
更新日期:2012-07-01 00:00:00
abstract::Spinocerebellar ataxia type 1 (SCA1) is one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine tract expansion. In SCA1, the expanded polyglutamine tract is in the ataxin-1 (ATXN1) protein. ATXN1 is part of an in vivo complex with retinoid acid receptor-related orphan receptor alpha (Rora)...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr108
更新日期:2011-06-01 00:00:00