<i>De Novo</i>Heterozygous Mutations in<i>SMC3</i>Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes

Gil-Rodríguez, María Concepción; Deardorff, Matthew A.; Ansari, Morad; Tan, Christopher; Parenti, Ilaria; Baquero-Montoya, Carolina; Ousager, Lilian Bomme; Puisac, Beatriz; Hernández-Marcos, María; Teresa-Rodrigo, María Esperanza; Marcos‐Alcalde, Íñigo; Wesselink, Jan Jaap; Lusa-Bernal, Silvia; Bijlsma, Emilia K.; Braunholz, Diana; Bueno-Martínez, Inés; Clark, Dinah; Cooper, N; Curry, Cynthia J.; Fisher, Richard; Fryer, Alan; Ganesh, Jaya; Gervasini, Cristina; Gillessen‐Kaesbach, Gabriele; Guo, Yiran; Hákonarson, Hákon; Hopkin, Robert J.; Kaur, Maninder; Keating, Brendan J.; Kibæk, Maria; Kinning, Esther; Kleefstra, Tjitske; Kline, Antonie D.; Kuchinskaya, Ekaterina; Larizza, Lidia; Li, Yun R.; Liu, Xuanzhu; Mariani, Milena; Picker, Jonathan; Pié, Ángeles; Pozojevic, Jelena; Queralt, Ethel; Richer, Julie; Roeder, Elizabeth; Sinha, Anubha; Scott, Richard; So, Joyce; Wusik, Katherine; Wilson, Louise C.; Zhang, Jianguo; Gómez‐Puertas, Paulino; Casale, César H.; Ström, Lena; Selicorni, Angelo; Ramos, Feliciano J.; Jackson, Laird G.; Krantz, Ian D.; Das, Soma; Hennekam, Raoul C. M.; Kaiser, Frank J.; FitzPatrick, David R.; Pié, Juan

doi:10.1002/humu.22761

Cited by 81 publications

(96 citation statements)

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“…To date, CdLS has been linked to mutations in genes encoding cohesin subunits SMC1A, 3 SMC3, 3,4 and RAD21, 5,6 the accessory protein NIPBL, 7−9 and the zinc-dependent deacetylase HDAC8. 10−12 Mutations in NIPBL are predominant in classical CdLS patients and account for about 60% of diagnosed cases, whereas mutations in the other genes are less frequent (5% for SMC1A, and about 5% for HDAC8, SMC3, and RAD21 together) and are seen in patients with more variant phenotypes.…”

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Biochemical and Structural Characterization of HDAC8 Mutants Associated with Cornelia de Lange Syndrome Spectrum Disorders

et al. 2015

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Cornelia de Lange Syndrome (CdLS) spectrum disorders are characterized by multiple organ system congenital anomalies that result from mutations in genes encoding core cohesin proteins SMC1A, SMC3, and RAD21, or proteins that regulate cohesin function such as NIPBL and HDAC8. HDAC8 is the Zn2+-dependent SMC3 deacetylase required for cohesin recycling during the cell cycle, and 17 different HDAC8 mutants have been identified to date in children diagnosed with CdLS. As part of our continuing studies focusing on aberrant HDAC8 function in CdLS, we now report the preparation and biophysical evaluation of five human HDAC8 mutants: P91L, G117E, H180R, D233G, and G304R. Additionally, the double mutants D233G-Y306F and P91L-Y306F were prepared to enable cocrystallization of intact enzyme–substrate complexes. X-ray crystal structures of G117E, P91L-Y306F, and D233G-Y306F HDAC8 mutants reveal that each CdLS mutation causes structural changes that compromise catalysis and/or thermostability. For example, the D233G mutation disrupts the D233-K202-S276 hydrogen bond network, which stabilizes key tertiary structure interactions, thereby significantly compromising thermostability. Molecular dynamics simulations of H180R and G304R HDAC8 mutants suggest that the bulky arginine side chain of each mutant protrudes into the substrate binding site and also causes active site residue Y306 to fluctuate away from the position required for substrate activation and catalysis. Significantly, the catalytic activities of most mutants can be partially or fully rescued by the activator N-(phenylcarbamothioyl)-benzamide, suggesting that HDAC8 activators may serve as possible leads in the therapeutic management of CdLS.

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Biochemical and Structural Characterization of HDAC8 Mutants Associated with Cornelia de Lange Syndrome Spectrum Disorders

et al. 2015

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“…Additionally, he had heart abnormalities with atrial and septal defects as well as developmental delays and a learning disability 12 . Clinical severity (CS) has been annotated according to Kline et al .…”

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confidence: 99%

“…The variant residues Smc1A-N1166T and Smc3-Q1147E have been found in patients with CdLS 12, 55, 56 whereas mutated amino acids Smc3-D1143H and Smc3-A1148T have been related to acute myeloid leukaemia 21, 54 and colorectal cancer 54, 57 , respectively. The mutant Smc3-Q1147E was previously reported to potentially be involved in maintaining the dimerization contact between the Smc1A-head and Smc3-head domains 12 . Interestingly, in the dynamic model, Smc3-Q1147 was found to be involved in correctly locating residues around Smc1A-K1120.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, the effect of the variant Smc3-Q1147E, found in a CdLS patient 12, 55, 56 has been analysed in detail, offering a functional explanation for the impaired behaviour of the protein and linking the change at this position to a defect in the activation of AS2 after activation of AS1. The highly reduced, but not completely inhibited, functionality of the complex could justify the clinical findings in this patient who was phenotypically classified as moderate according to Kline et al .…”

Section: Discussionmentioning

confidence: 99%

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Two-step ATP-driven opening of cohesin head

Marcos‐Alcalde

Mendieta‐Moreno

Puisac³

et al. 2017

Sci Rep

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The cohesin ring is a protein complex composed of four core subunits: Smc1A, Smc3, Rad21 and Stag1/2. It is involved in chromosome segregation, DNA repair, chromatin organization and transcription regulation. Opening of the ring occurs at the “head” structure, formed of the ATPase domains of Smc1A and Smc3 and Rad21. We investigate the mechanisms of the cohesin ring opening using techniques of free molecular dynamics (MD), steered MD and quantum mechanics/molecular mechanics MD (QM/MM MD). The study allows the thorough analysis of the opening events at the atomic scale: i) ATP hydrolysis at the Smc1A site, evaluating the role of the carboxy-terminal domain of Rad21 in the process; ii) the activation of the Smc3 site potentially mediated by the movement of specific amino acids; and iii) opening of the head domains after the two ATP hydrolysis events. Our study suggests that the cohesin ring opening is triggered by a sequential activation of the ATP sites in which ATP hydrolysis at the Smc1A site induces ATPase activity at the Smc3 site. Our analysis also provides an explanation for the effect of pathogenic variants related to cohesinopathies and cancer.

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“…Interestingly, female CdLS probands with an SMC1A mutation tend to show a more severe phenotype compared to males with SMC1A mutations [Deardorff et al, 2007]. SMC1A and SMC3 mutations found in individuals with CdLS were missense mutations or in-frame deletions [Deardorff et al, 2007;Gil-Rodríguez et al, 2015]. Recently, female probands with heterozygous loss-of-function mutations in SMC1A were found in association with seizures and intellectual disability without a clear CdLS phenotype [Goldstein et al, 2015;Lebrun et al, 2015;Jansen et al, 2016].…”

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Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes

Izumi

2016

Mol Syndromol

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Some genetic disorders caused by mutations in genes encoding components of the transcriptional machinery as well as proteins involved in epigenetic modification of the genome share many overlapping features, such as facial dysmorphisms, growth problems and developmental delay/intellectual disability. As a basis for some shared phenotypic characteristics in these syndromes, a similar transcriptome disturbance, characterized by global transcriptional dysregulation, is believed to play a major role. In this review article, a general overview of gene transcription is provided, and the current knowledge of the mechanisms underlying some disorders of transcriptional regulation, such as Rubinstein- Taybi, Coffin-Siris, Cornelia de Lange, and CHOPS syndromes, are discussed.

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De NovoHeterozygous Mutations inSMC3Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes

Cited by 81 publications

References 51 publications

Biochemical and Structural Characterization of HDAC8 Mutants Associated with Cornelia de Lange Syndrome Spectrum Disorders

Biochemical and Structural Characterization of HDAC8 Mutants Associated with Cornelia de Lange Syndrome Spectrum Disorders

Two-step ATP-driven opening of cohesin head

Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes

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