scholarly journals Thrombocytopenia Microcephaly Syndrome - a novel phenotype associated withACTBmutations

2018 ◽  
Author(s):  
Sharissa L. Latham ◽  
Nadja Ehmke ◽  
Patrick Y.A. Reinke ◽  
Manuel H. Taft ◽  
Michael J. Lyons ◽  
...  
Keyword(s):  
Developmental Disorder ◽  
Germ Line ◽  
Interaction Network ◽  
Md Simulations ◽  
Clinical Syndrome ◽  
Actin Binding ◽  
Coding Region ◽  
Phenotype Correlation ◽  
Cytoplasmic Actin ◽  
Complex Developmental Disorder

Introductory paragraphUntil recently missense germ-line mutations inACTB, encoding the ubiquitously expressed β-cytoplasmic actin (CYA), were exclusively associated with Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF), a complex developmental disorder1,2. Here, we report six patients with previously undescribed heterozygous variants clustered in the 3’-coding region ofACTB. These patients present with clinical features different from BWCFF, including thrombocytopenia, microcephaly, and mild developmental disability. Patient derived cells are morphologically and functionally distinct from controls. Assessment of cytoskeletal constituents identified a discrete filament population altered in these cells, which comprises force generating and transmitting actin binding proteins (ABP) known to be associated with thrombocytopenia3–8.In silicomodelling and molecular dynamics (MD)-simulations support altered interactions between these ABP and mutant β-CYA. Our results describe a new clinical syndrome associated withACTBmutations with a distinct genotype-phenotype correlation, identify a cytoskeletal protein interaction network crucial for thrombopoiesis, and provide support for the hypomorphic nature of these actinopathy mutations.

Das Konzept der «Multiple Complex Developmental Disorder» (MCDD)

2012 ◽  
Vol 40 (5) ◽  
pp. 341-349 ◽  
Author(s):  
Inge Kamp-Becker ◽  
Klaus Baumann ◽  
Linda Sprenger ◽  
Katja Becker
Keyword(s):  
Developmental Disorder ◽  
Wird Eine ◽  
Icd 10 ◽  
Dsm Iv ◽  
Multiple Complex Developmental Disorder ◽  
Complex Developmental Disorder

Fragestellung: Die «Multiple complex developmental disorder» (MCDD) ist ein wenig bekanntes Störungsbild, das durch Auffälligkeiten in der Emotionsregulation, der sozialen Interaktion und Denkstörungen gekennzeichnet ist. Weder im Klassifikationssystem des ICD-10, noch im DSM-IV kommt diese Diagnose vor. Methodik: In der vorliegenden Arbeit wird eine Übersicht über die diagnostischen Kriterien und den aktuellen Forschungsstand zum Konzept der MCDD gegeben und anhand einer Kasuistik eines 17-jährigen Jugendlichen illustriert. Ergebnis: Das Störungsbild der MCDD weist Überschneidungen zu autistischen Störungen, aber auch zu Störungen aus dem schizophrenen Formenkreis auf. Eine klare Abgrenzung bzw. Zuordnung ist bisher nicht eindeutig möglich. Schlussfolgerungen: Viele Fragen bezüglich des Störungsbildes bleiben offen, weitere Forschung ist hier vonnöten.

scholarly journals Non-coding region variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms

2021 ◽  
Author(s):  
Caroline F. Wright ◽  
Nicholas M. Quaife ◽  
Laura Ramos-Hernández ◽  
Petr Danecek ◽  
Matteo P. Ferla ◽  
...  
Keyword(s):  
Developmental Disorder ◽  
Loss Of Function ◽  
Coding Region

Unresponsiveness to psychosocial stress in a subgroup of autistic-like children, Multiple Complex Developmental Disorder

2000 ◽  
Vol 25 (8) ◽  
pp. 753-764 ◽  
Author(s):  
L.M.C Jansen ◽  
C.C Gispen-de Wied ◽  
R.J Van der Gaag ◽  
F ten Hove ◽  
S.W.M Willemsen-Swinkels ◽  
...  
Keyword(s):  
Psychosocial Stress ◽  
Developmental Disorder ◽  
Multiple Complex Developmental Disorder ◽  
Complex Developmental Disorder

scholarly journals Mechanosensing through direct binding of tensed F-actin by LIM domains

2020 ◽  
Author(s):  
Xiaoyu Sun ◽  
Donovan Y. Z. Phua ◽  
Lucas Axiotakis ◽  
Mark A. Smith ◽  
Elizabeth Blankman ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Point Mutations ◽  
Cytoskeletal Proteins ◽  
Actin Binding ◽  
General Mechanism ◽  
Protein Protein Interaction ◽  
Cytoplasmic Actin ◽  
Lim Domains ◽  
Lim Proteins

SummaryMechanical signals transmitted through the cytoplasmic actin cytoskeleton must be relayed to the nucleus to control gene expression. LIM domains are protein-protein interaction modules found in cytoskeletal proteins and transcriptional regulators; however, it is unclear if there is a direct link between these two functions. Here we identify three LIM protein families (zyxin, paxillin, and FHL) whose members preferentially localize to the actin cytoskeleton in mechanically-stimulated cells through their tandem LIM domains. A minimal actin-myosin reconstitution system reveals that representatives of all three families directly bind F-actin only in the presence of mechanical force. Point mutations at a site conserved in each LIM domain of these proteins selectively disrupt tensed F-actin binding in vitro and cytoskeletal localization in cells, demonstrating a common, avidity-based mechanism. Finally, we find that binding to tensed F-actin in the cytoplasm excludes the cancer-associated transcriptional co-activator FHL2 from the nucleus in stiff microenvironments. This establishes direct force-activated F-actin binding by FHL2 as a mechanosensing mechanism. Our studies suggest that force-dependent sequestration of LIM proteins on the actin cytoskeleton could be a general mechanism for controlling nuclear localization to effect mechanical signaling.

scholarly journals Identification and sequence analysis of a new member of the mouse HSP70 gene family and characterization of its unique cellular and developmental pattern of expression in the male germ line.

1988 ◽  
Vol 8 (7) ◽  
pp. 2925-2932 ◽  
Author(s):  
Z F Zakeri ◽  
D J Wolgemuth ◽  
C R Hunt
Keyword(s):  
Heat Shock ◽  
Gene Family ◽  
Developmental Stages ◽  
Germ Line ◽  
Cell Lineage ◽  
Hsp70 Gene ◽  
Coding Region ◽  
Male Germ Line ◽  
Sequence Organization

A unique member of the mouse HSP70 gene family has been isolated and characterized with respect to its DNA sequence organization and expression. The gene contains extensive similarity to a heat shock-inducible HSP70 gene within the coding region but diverges in both 3' and 5' nontranslated regions. The gene does not yield transcripts in response to heat shock in mouse L cells. Rather, the gene appears to be activated uniquely in the male germ line. Analysis of RNA from different developmental stages and from enriched populations of spermatogenic cells revealed that this gene is expressed during the prophase stage of meiosis. A transcript different in size from the major heat-inducible mouse transcripts is most abundant in meiotic prophase spermatocytes and decreases in abundance in postmeiotic stages of spermatogenesis. This pattern of expression is distinct from that observed for another member of this gene family, which was previously shown to be expressed abundantly in postmeiotic germ cells. These observations suggest that specific HSP70 gene family members play distinct roles in the differentiation of the germ cell lineage in mammals.

scholarly journals Modulating dynamics and function of nuclear actin with synthetic bicyclic peptides

2020 ◽  
Author(s):  
Nanako Machida ◽  
Daisuke Takahashi ◽  
Yuya Ueno ◽  
Yoshihiro Nakama ◽  
Raphael J Gubeli ◽  
...  
Keyword(s):  
Regulation Of Gene Expression ◽  
Living Cells ◽  
Actin Binding ◽  
Nuclear Actin ◽  
Dna Double Strand Breaks ◽  
Cytoplasmic Actin ◽  
Localization Signal ◽  
Dynamics And Function ◽  
And Function ◽  
Analytical Tools

Abstract Actin exists in monomeric globular (G-) and polymerized filamentous (F-) forms and the dynamics of its polymerization/depolymerization are tightly regulated in both the cytoplasm and the nucleus. Various essential functions of nuclear actin have been identified including regulation of gene expression and involvement in the repair of DNA double-strand breaks (DSB). Small G-actin-binding molecules affect F-actin formation and can be utilized for analysis and manipulation of actin in living cells. However, these G-actin-binding molecules are obtained by extraction from natural sources or through complex chemical synthesis procedures, and therefore, the generation of their derivatives for analytical tools is underdeveloped. In addition, their effects on nuclear actin cannot be separately evaluated from those on cytoplasmic actin. Previously, we have generated synthetic bicyclic peptides, consisting of two macrocyclic rings, which bind to G-actin but not to F-actin. Here, we describe the introduction of these bicyclic peptides into living cells. Furthermore, by conjugation to a nuclear localization signal (NLS), the bicyclic peptides accumulated in the nucleus. The NLS-bicyclic peptides repress the formation of nuclear F-actin, and impair transcriptional regulation and DSB repair. These observations highlight a potential role for NLS-linked bicyclic peptides in the manipulation of dynamics and functions of nuclear actin.

scholarly journals Transgenic expression of the muscle-specific intermediate filament protein desmin in nonmuscle cells.

1989 ◽  
Vol 108 (3) ◽  
pp. 1009-1024 ◽  
Author(s):  
F R Pieper ◽  
G Schaart ◽  
P J Krimpenfort ◽  
J B Henderik ◽  
H J Moshage ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Intermediate Filament ◽  
Germ Line ◽  
Fibroblast Cell ◽  
Intermediate Filament Protein ◽  
Coding Region ◽  
Tissue Specific ◽  
Nonmuscle Cells ◽  
Filament Protein ◽  
Vimentin Gene

The coding region of the hamster desmin gene was fused to the 5' flanking sequences of the hamster vimentin gene and introduced into the germ line of mice. The expression of this intermediate filament gene construct (pVDes) was analyzed at the RNA and protein level in transgenic mice as well as in fibroblast cell lines and primary hepatocyte cultures derived from these mice. In all transgenic mice, the pVDes-encoded protein was coexpressed with mouse vimentin in a tissue-specific fashion and was indistinguishable from normal hamster desmin. Culturing of transgenic hepatocytes induced desmin expression indicating that 3.2 kbp of the vimentin gene 5' region regulates both tissue-specific and tissue culture-induced intermediate filament protein expression. Immunohistochemical staining and double-label immunoelectron microscopy of cultured transgenic fibroblasts showed that the pVDes protein assembled into intermediate filaments which colocalized with the mouse vimentin filaments. Endogenous vimentin RNA levels were not influenced by high-level pVDes expression. The coexpression of desmin and vimentin in nonmuscle cells did not result in detectable developmental, morphological, or physiological abnormalities.

MRI-based morphometry in children with multiple complex developmental disorder, a phenotypically defined subtype of pervasive developmental disorder not otherwise specified

2007 ◽  
Vol 38 (9) ◽  
pp. 1361-1367 ◽  
Author(s):  
B. E. Lahuis ◽  
S. Durston ◽  
H. Nederveen ◽  
M. Zeegers ◽  
S. J. M. C. Palmen ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Pervasive Developmental Disorder ◽  
Developmental Disorder ◽  
Autism Spectrum ◽  
Intracranial Volume ◽  
High Functioning ◽  
Not Otherwise Specified ◽  
Multiple Complex Developmental Disorder ◽  
Spectrum Disorders ◽  
Complex Developmental Disorder

BackgroundThe DSM-IV-R classification Pervasive Developmental Disorder – Not otherwise Specified (PDD-NOS) is based on the symptoms for autism and includes a wide variety of phenotypes that do not meet full criteria for autism. As such, PDD-NOS is a broad and poorly defined residual category of the autism spectrum disorders. In order to address the heterogeneity in this residual category it may be helpful to define clinical and neurobiological subtypes. Multiple complex developmental disorder (MCDD) may constitute such a subtype. In order to study the neurobiological specificity of MCDD in comparison with other autism spectrum disorders, we investigated brain morphology in children (age 7–15 years) with MCDD compared to children with autism and typically developing controls.MethodStructural MRI measures were compared between 22 high-functioning subjects with MCDD and 21 high-functioning subjects with autism, and 21 matched controls.ResultsSubjects with MCDD showed an enlarged cerebellum and a trend towards larger grey-matter volume compared to control subjects. Compared to subjects with autism, subjects with MCDD had smaller intracranial volume.ConclusionsWe report a pattern of volumetric changes in the brains of subjects with MCDD, similar to that seen in autism. However, no enlargement in head size was found. This suggests that although some of the neurobiological changes associated with MCDD overlap with those in autism, others do not. These neurobiological changes may reflect differences in the developmental trajectories associated with these two subtypes of autism spectrum disorders.

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