Abstract:
:The congenital malformation split hand/foot (SHFM) is characterized by missing central fingers and dysmorphology or fusion of the remaining ones. Type-1 SHFM is linked to deletions/rearrangements of the DLX5-DLX6 locus and point mutations in the DLX5 gene. The ectrodactyly phenotype is reproduced in mice by the double knockout (DKO) of Dlx5 and Dlx6. During limb development, the apical ectodermal ridge (AER) is a key-signaling center responsible for early proximal-distal growth and patterning. In Dlx5;6 DKO hindlimbs, the central wedge of the AER loses multilayered organization and shows down-regulation of FGF8 and Dlx2. In search for the mechanism, we examined the non-canonical Wnt signaling, considering that Dwnt-5 is a target of distalless in Drosophila and the knockout of Wnt5, Ryk, Ror2 and Vangl2 in the mouse causes severe limb malformations. We found that in Dlx5;6 DKO limbs, the AER expresses lower levels of Wnt5a, shows scattered β-catenin responsive cells and altered basolateral and planar cell polarity (PCP). The addition of Wnt5a to cultured embryonic limbs restored the expression of AER markers and its stratification. Conversely, the inhibition of the PCP molecule c-jun N-terminal kinase caused a loss of AER marker expression. In vitro, the addition of Wnt5a on mixed primary cultures of embryonic ectoderm and mesenchyme was able to confer re-polarization. We conclude that the Dlx-related ectrodactyly defect is associated with the loss of basoapical and PCP, due to reduced Wnt5a expression and that the restoration of the Wnt5a level is sufficient to partially reverts AER misorganization and dysmorphology.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Conte D,Garaffo G,Lo Iacono N,Mantero S,Piccolo S,Cordenonsi M,Perez-Morga D,Orecchia V,Poli V,Merlo GRdoi
10.1093/hmg/ddv514subject
Has Abstractpub_date
2016-02-15 00:00:00pages
740-54issue
4eissn
0964-6906issn
1460-2083pii
ddv514journal_volume
25pub_type
杂志文章abstract::Microdeletion at chromosomal position 15q13.3 has been described in intellectual disability, autism spectrum disorders, schizophrenia and recently in idiopathic generalized epilepsy (IGE). Using independent IGE cohorts, we first aimed to confirm the association of 15q13.3 deletions and IGE. We then set out to determin...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddp311
更新日期:2009-10-01 00:00:00
abstract::The success of the human genome sequencing project has created wide-spread interest in exploring the human epigenome in order to elucidate how the genome executes the information it holds. Although all (nucleated) human cells effectively contain the same genome, they contain very different epigenomes depending upon ce...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddi110
更新日期:2005-04-15 00:00:00
abstract::Promising results in several clinical studies have emphasized the potential of gene therapy to address important medical needs and initiated a surge of investments in drug development and commercialization. This enthusiasm is driven by positive data in clinical trials including gene replacement for Hemophilia B, X-lin...
journal_title:Human molecular genetics
pub_type: 杂志文章,评审
doi:10.1093/hmg/ddv451
更新日期:2016-04-15 00:00:00
abstract::Pathogenic leucine-rich repeat kinase 2 (LRRK2) mutations are recognized as the most common cause of familial Parkinson's disease in certain populations. Recently, LRRK2 mutations were shown to be associated with a higher risk of hormone-related cancers. However, how LRRK2 itself contributes to cancer risk remains unk...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx337
更新日期:2017-11-15 00:00:00
abstract::Gene mutations that encode retinoschisin (RS1) cause X-linked retinoschisis (XLRS), a form of juvenile macular and retinal degeneration that affects males. RS1 is an adhesive protein which is proposed to preserve the structural and functional integrity of the retina, but there is very little evidence of the mechanism ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq006
更新日期:2010-04-01 00:00:00
abstract::The striated muscle sarcomeres are highly organized structures composed of actin (thin) and myosin (thick) filaments that slide past each other during contraction. The integrity of sarcomeres is controlled by a set of structural proteins, among which are titin, a giant molecule that contains several immunoglobulin (Ig...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.7.1329
更新日期:1999-07-01 00:00:00
abstract::The early growth response 2 gene ( EGR2 ) is a Cys2His2zinc finger transcription factor which is thought to play a role in the regulation of peripheral nervous system myelination. This idea is based partly on the phenotype of homozygous Krox20 ( Egr2 ) knockout mice, which display hypomyelination of the PNS and a bloc...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.7.1245
更新日期:1999-07-01 00:00:00
abstract::Slow-channel syndrome (SCS) is a congenital myasthenic disorder caused by point mutations in subunits of skeletal muscle acetylcholine receptor leading to Ca(2+) overload and degeneration of the postsynaptic membrane, nuclei and mitochondria of the neuromuscular junction (NMJ). In both SCS muscle biopsies and transgen...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddt397
更新日期:2014-01-01 00:00:00
abstract::Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ≃25 000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (RO...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa255
更新日期:2020-12-08 00:00:00
abstract::Waardenburg syndrome type 2 (WS2) is an autosomal dominant disorder characterized by a combination of pigmentary and auditory abnormalities. Approximately 20% of WS2 cases are associated with mutations in the gene encoding microphthalmia-associated transcription factor (MITF). MITF plays a critical role in the develop...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.8.1431
更新日期:1999-08-01 00:00:00
abstract::Parkin is a multifunctional protein, including maintaining mitochondrial homeostasis. Recent evidence suggests that Parkin is recruited from the cytoplasm to damaged mitochondria with low membrane potential. We found that intracellular localization of Parkin changed with cellular growth phase. Parkin was preferentiall...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr530
更新日期:2012-03-01 00:00:00
abstract::Deficiency of the dysferlin protein presents as two major clinical phenotypes: limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Dysferlin is known to participate in membrane repair, providing a potential hypothesis to the underlying pathophysiology of these diseases. The size of the dysferlin cDNA prevents...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq065
更新日期:2010-05-15 00:00:00
abstract::Development of neural circuitry depends on the integration of signaling pathways to coordinate specification, proliferation and differentiation of cell types in the right number, in the right place, at the right time. Zinc finger protein 423 (Zfp423), a 30-zinc finger transcription factor, forms alternate complexes wi...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr300
更新日期:2011-10-01 00:00:00
abstract::F1Fo-ATP synthase is a key enzyme of mitochondrial energy provision producing most of cellular ATP. So far, mitochondrial diseases caused by isolated disorders of the ATP synthase have been shown to result from mutations in mtDNA genes for the subunits ATP6 and ATP8 or in nuclear genes encoding the biogenesis factors ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddq254
更新日期:2010-09-01 00:00:00
abstract::We have studied the dynamics of mitochondrial DNA maintenance and segregation in human cells using serial cybrid transfer of partially duplicated mitochondrial DNA, from a mitochondrial myopathy patient, to two distinct recipient cell types. The results indicate two radically different outcomes dependent upon nuclear ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.8.1251
更新日期:1997-08-01 00:00:00
abstract::Mucopolysaccharidosis type VI (MPS-VI), caused by mutational inactivation of the glycosaminoglycan-degrading enzyme arylsulfatase B (Arsb), is a lysosomal storage disorder primarily affecting the skeleton. We have previously reported that Arsb-deficient mice display high trabecular bone mass and impaired skeletal grow...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddaa006
更新日期:2020-03-27 00:00:00
abstract::Maintenance of an intact mitochondrial genome is essential for oxidative phosphorylation in all eukaryotes. Depletion of mitochondrial genome copy number can have severe pathological consequences due to loss of respiratory capacity. In Saccharomyces cerevisiae, several bifunctional metabolic enzymes have been shown to...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn313
更新日期:2009-01-01 00:00:00
abstract::Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genom...
journal_title:Human molecular genetics
pub_type: 杂志文章,meta分析
doi:10.1093/hmg/ddu150
更新日期:2014-08-15 00:00:00
abstract::Ciliary trafficking defects are the underlying cause of many ciliopathies, including Retinitis Pigmentosa (RP). Anterograde intraflagellar transport (IFT) is mediated by kinesin motor proteins; however, the function of the homodimeric Kif17 motor in cilia is poorly understood, whereas Kif7 is known to play an importan...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx143
更新日期:2017-07-01 00:00:00
abstract::Genomic imprinting is a phenomenon whereby monoallelic gene expression occurs in a parent-of-origin-specific manner. A subset of imprinted genes acquires a tissue-specific imprinted status during the course of tissue development, and this process can be analyzed by means of an in vitro differentiation system utilizing...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr577
更新日期:2012-03-15 00:00:00
abstract::Mutation analysis was performed on DNA samples of 965 individuals from four different ethnic groups in South Africa, in an attempt to determine the spectrum of sequence variants in the haemochromatosis ( HFE ) gene. This population screening approach, utilizing a combined heteroduplex and single-strand conformation po...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/8.8.1517
更新日期:1999-08-01 00:00:00
abstract::We previously identified Peg1/Mest as a novel paternally expressed gene in the developing mouse embryo. The human PEG1 gene was recently assigned to 7q32 and shown to be imprinted and paternally expressed. Therefore, PEG1 deficiency could participate in the aetiology of pre- and post-natal growth retardation associate...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/6.11.1907
更新日期:1997-10-01 00:00:00
abstract::Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene account for >70% of X-linked retinitis pigmentosa (XLRP) and 15-20% of all inherited retinal degeneration. Gene replacement therapy for RPGR-XLRP was hampered by the relatively slow disease progression in mouse models and by difficulties in cloning the...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv134
更新日期:2015-07-15 00:00:00
abstract::The purpose of this study was to determine whether thrombospondin (TSP)-1 promotes macrophage activity and disease progression in dysferlinopathy. First, we found that levels of TSP-1 are elevated in blood of non-ambulant dysferlinopathy patients compared with ambulant patients and healthy controls, supporting the ide...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddx378
更新日期:2017-12-15 00:00:00
abstract::A functional genetic screen using loss-of-function and gain-of-function alleles was performed to identify modifiers of tau-induced neurotoxicity using the 2N/4R (full-length) isoform of wild-type human tau expressed in the fly retina. We previously reported eye pigment mutations, which create dysfunctional lysosomes, ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddr432
更新日期:2011-12-15 00:00:00
abstract::Acetazolamide responsive hereditary paroxysmal cerebellar ataxia (APCA) is a rare autosomal dominant disorder characterized by attacks of cerebellar ataxia and dysarthria with normal or near normal neurologic function between attacks. A genome-wide search using polymorphic di- and tri-nucleotide repeats was initiated ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/4.2.279
更新日期:1995-02-01 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP) are two neurodegenerative disorders characterized by the accumulation of TDP-43. TDP-43 is proteolitically cleaved to generate two major C-terminal fragments of 35 and 25 kDa. The latter, known as TDP-25, is a consistent feature of FT...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv193
更新日期:2015-08-15 00:00:00
abstract::There are two known mRNA degradation pathways, 3' to 5' and 5' to 3'. We identified likely pathogenic variants in two genes involved in these two pathways in individuals with intellectual disability. In a large family with multiple branches, we identified biallelic variants in DCPS in three affected individuals; a spl...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddv069
更新日期:2015-06-01 00:00:00
abstract::We have previously developed a functional assay in yeast for the copper transporter, ATP7B, defective in Wilson disease (WND). Analysis of WND variant ATP7B proteins revealed that several were able to completely, or nearly completely, complement a mutant yeast strain in which the ATP7B ortholog CCC2 was disrupted, ind...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/9.13.1927
更新日期:2000-08-12 00:00:00
abstract::Sphingosine-1-phosphate (S1P) is a lipid-signaling molecule produced by sphingosine kinase in response to a wide number of stimuli. By acting through a family of widely expressed G protein-coupled receptors, S1P regulates diverse physiological processes. Here we examined the role of S1P signaling in neurodegeneration ...
journal_title:Human molecular genetics
pub_type: 杂志文章
doi:10.1093/hmg/ddn126
更新日期:2008-08-01 00:00:00