When chromatin organisation floats astray: the<i>Srcap</i>gene and Floating–Harbor syndrome

Messina, Giovanni; Atterrato, Maria Teresa; Dimitri, Patrizio

doi:10.1136/jmedgenet-2016-103842

Cited by 35 publications

(34 citation statements)

References 47 publications

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“…This group of syndromes can be caused by mutations in genes important for genome or nuclear stability (3M syndrome [78–80], Cornelia de Lange syndrome [81], Hutchinson-Gilford Progeria [82–83], microcephalic osteodysplastic primordial dwarfism type 2, MOPD II [67–68], SOFT syndrome [84–85]), chromatin remodeling (Floating-Harbor syndrome [86–88], Coffin-Siris syndrome [89]), RNA processing (microcephalic osteodysplastic primordial dwarfism type 1, MOPD I [90–91]), ubiquitination (Mulibrey nanism [92–94]), cytoskeletal interaction (primordial dwarfism due to CRIPT mutation [95]), microtubule organization (Alström syndrome [96]) or cholesterol biosynthesis (Smith-Lemli-Opitz syndrome [97], (Table 1). The patients are often born small for gestational age indicating that growth is affected during intrauterine life.…”

Section: Genetics Of Short Staturementioning

confidence: 99%

Genetics of Short Stature

Jee¹,

Andrade

Baron³

et al. 2017

Endocrinology and Metabolism Clinics of North America

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Synopsis Short stature is a common and heterogeneous condition which is often genetic in etiology. For most children with genetic short stature, the specific molecular causes remain unknown, but with advances in exome/genome sequencing and bioinformatics approaches, new genetic causes of growth disorders have been identified, contributing to the understanding of the underlying molecular mechanisms of longitudinal bone growth and growth failure. These genetic causes can involve not only hormonal deficiencies, including the growth hormone-IGF-1 axis, thyroid hormone or glucocorticoid and defects in hormonal receptors or subsequent signaling, but also defects in fundamental cellular processes (intracellular signaling pathways, transcriptional regulation, and DNA repair), extracellular matrix, or paracrine signaling. Especially, heterozygous and/or mild mutations in SHOX, NPR2, ACAN, IGF1, IGF1R, or FGFR3 have been associated with isolated short stature without other prominent or noticeable phenotype while homozygous and/or severe mutations in these genes cause severe short stature with bone malformation, that is, a chondrodysplasia. Identifying new genetic causes of growth disorders has the potential to improve diagnosis, prognostic accuracy, individualized management, and help avoid unnecessary testing for endocrine and other disorders.

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Section: Genetics Of Short Staturementioning

confidence: 99%

Genetics of Short Stature

Jee¹,

Andrade

Baron³

et al. 2017

Endocrinology and Metabolism Clinics of North America

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“…Over the last decade, growing evidence has shown that mutations in genes which encode the epigenetic regulators controlling chromatin configuration can promote cancer and human developmental disorders23456789. An emblematic case of these “chromatin diseases” is the developmental genetic syndrome called CHARGE10, which is caused by mutations in the gene encoding a member of the CHD family of ATP-dependent chromatin remodeling enzymes411.…”

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confidence: 99%

“…Intriguingly, truncating mutations of the Srcap gene cause the rare Floating Harbor syndrome that, among other defects, includes craniofacial abnormalities9.…”

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confidence: 99%

The human Cranio Facial Development Protein 1 (Cfdp1) gene encodes a protein required for the maintenance of higher-order chromatin organization

Messina

Atterrato

Prozzillo

et al. 2017

Sci Rep

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The human Cranio Facial Development Protein 1 (Cfdp1) gene maps to chromosome 16q22.2-q22.3 and encodes the CFDP1 protein, which belongs to the evolutionarily conserved Bucentaur (BCNT) family. Craniofacial malformations are developmental disorders of particular biomedical and clinical interest, because they represent the main cause of infant mortality and disability in humans, thus it is important to understand the cellular functions and mechanism of action of the CFDP1 protein. We have carried out a multi-disciplinary study, combining cell biology, reverse genetics and biochemistry, to provide the first in vivo characterization of CFDP1 protein functions in human cells. We show that CFDP1 binds to chromatin and interacts with subunits of the SRCAP chromatin remodeling complex. An RNAi-mediated depletion of CFDP1 in HeLa cells affects chromosome organization, SMC2 condensin recruitment and cell cycle progression. Our findings provide new insight into the chromatin functions and mechanisms of the CFDP1 protein and contribute to our understanding of the link between epigenetic regulation and the onset of human complex developmental disorders.

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“…In the last few decades, a large body of experimental evidence has suggested that mutations in genes encoding a variety of chromatin factors and epigenetic regulators, such as DNA or histone modifying enzymes and members of ATP-dependent chromatin remodeling complexes, are crucial players in human genetic diseases and cancer (1)(2)(3)(4)(5)(6)(7). Floating-Harbor syndrome (FHS), also known as Pelletier-Leisti syndrome, is a human developmental disorder characterized by delayed bone mineralization and growth deficiency, which are often associated with mental retardation and skeletal and craniofacial abnormalities (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

“…FHS has a dominant inheritance pattern caused by nonsense or frameshift mutations in exons 33 and 34 of Srcap. (9,11). These mutations are supposed to produce a C-terminal-truncated SRCAP protein variant missing the AT-hook motifs with DNA-binding activity and are possibly responsible for a dominant negative effect (9,11) triggering the onset of FHS.…”

Section: Introductionmentioning

confidence: 99%

ATPase SRCAP is a new player in cell division, uncovering molecular aspects of Floating-Harbor syndrome

Messina

Prozzillo

et al. 2020

Preprint

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Floating-Harbor syndrome (FHS) is a rare inherited developmental disorder characterized by bone mineralization delay and growth deficits frequently associated with skeletal and craniofacial defects and mental retardation. The major cause of FHS is heterozygous truncating mutations in Srcap, which encodes the ATPase SRCAP, the core catalytic subunit of the homonymous multiprotein chromatin-remodeling complex in humans. This complex promotes the exchange of canonical histone H2A with the H2A.Z variant. SRCAP is also implicated in several cellular processes, but the molecular basis of FHS still needs to be elucidated. Using a combined approach, we studied the involvement of SRCAP in cell cycle progression in HeLa cells. In addition to the canonical localization in interphase nuclei, both SRCAP and its Drosophila orthologue localized to the mitotic apparatus after nuclear envelope breakdown, and their depletion impaired mitosis progression and cytokinesis in human and Drosophila cells, respectively. Importantly, SRCAP interacted with cytokinesis regulators and α-Tubulin during telophase, strongly supporting a direct role in cytokinesis, independent of its chromatin remodeling functions. Our results provide clues about previously undetected, evolutionarily conserved roles of SRCAP in ensuring proper mitosis and cytokinesis. We propose that perturbations in cell division contribute to the onset of developmental defects characteristic of FHS.

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When chromatin organisation floats astray: theSrcapgene and Floating–Harbor syndrome

Cited by 35 publications

References 47 publications

Genetics of Short Stature

Genetics of Short Stature

The human Cranio Facial Development Protein 1 (Cfdp1) gene encodes a protein required for the maintenance of higher-order chromatin organization

ATPase SRCAP is a new player in cell division, uncovering molecular aspects of Floating-Harbor syndrome

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