The Experts below are selected from a list of 1971 Experts worldwide ranked by ideXlab platform
Raoul C.m. Hennekam - One of the best experts on this subject based on the ideXlab platform.
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Co-occurrence of severe Goltz-Gorlin Syndrome and pentalogy of Cantrell - Case report and review of the literature.
American journal of medical genetics. Part A, 2011Co-Authors: Robert Smigiel, Aleksandra Jakubiak, Maria Paola Lombardi, Wojciech Jaworski, Ryszard Slezak, Dariusz Patkowski, Raoul C.m. HennekamAbstract:Goltz-Gorlin Syndrome is a highly variable disorder affecting many body parts of meso-ectodermal origin. Mutations in X-linked PORCN have been identified in almost all patients with a classical Goltz-Gorlin phenotype. The pentalogy of Cantrell is an infrequently described congenital disorder characterized by the combination of five anomalies: a midline supra-umbilical abdominal wall defect; absent or cleft lower part of the sternum; deficiency of the diaphragmatic pericardium; deficiency of the anterior diaphragm; and congenital heart anomalies. Etiology and pathogenesis are unknown. We report on an infant with findings fitting both Goltz-Gorlin Syndrome (sparse hair; anophthalmia; clefting; bifid nose; irregular vermillion of both lips; asymmetrical limb malformations; caudal appendage; linear aplastic skin defects; unilateral hearing loss) and the pentalogy of Cantrell (absent lower sternum; anterior diaphragmatic hernia; ectopia cordis; omphalocele). The clinical diagnosis Goltz-Gorlin Syndrome was confirmed molecularly by a point mutation in PORCN (c.727C>T). The presence of molecularly confirmed Goltz-Gorlin Syndrome and pentalogy of Cantrell in a single patient has been reported twice before. The present patient confirms that the pentalogy of Cantrell can be caused in some patients by a PORCN mutation. It remains at present uncertain whether this can be explained by the type or localization of the mutation within PORCN, or whether the co-occurrence of the two entities is additionally determined by mutations or polymorphisms in other genes, environmental factors, and/or epigenetic influences.
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phenotype and genotype in 17 patients with goltz Gorlin Syndrome
Journal of Medical Genetics, 2009Co-Authors: Saskia M Maas, Maria Paola Lombardi, Raoul C.m. Hennekam, A J Van Essen, Emma L Wakeling, Bruce Castle, I K Temple, V K A Kumar, Karin WritzlAbstract:Background: Goltz-Gorlin Syndrome or focal dermal hypoplasia is a highly variable, X-linked dominant Syndrome with abnormalities of ectodermal and mesodermal origin. In 2007, mutations in the PORCN gene were found to be causative in Goltz-Gorlin Syndrome. Method: A series of 17 patients with Goltz-Gorlin Syndrome is reported on, and their phenotype and genotype are described. Results: In 14 patients (13 females and one male), a PORCN mutation was found. Mutations included nonsense (n = 5), frameshift (n = 2), aberrant splicing (n = 2) and missense (n = 5) mutations. No genotype-phenotype correlation was found. All patients with the classical features of the Syndrome had a detectable mutation. In three females with atypical signs, no mutation was found. The male patient had classical features and showed mosaicism for a PORCN nonsense mutation in fibroblasts. Two affected sisters had a mutation not detectable in their parents, supporting germline mosaicism. Their father had undergone radiation for testicular cancer in the past. Two classically affected females had three severely affected female fetuses which all had midline thoracic and abdominal wall defects, resembling the pentalogy of Cantrell and the limb-body wall complex. Thoracic and abdominal wall defects were also present in two surviving patients. PORCN mutations can possibly cause pentalogy of Cantrell and limb-body wall complexes as well. Therefore, particularly in cases with limb defects, it seems useful to search for these. Conclusions: PORCN mutations can be found in all classically affected cases of Goltz-Gorlin Syndrome, including males. Somatic and germline mosaicism occur. There is no evident genotype-phenotype correlation.
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meier Gorlin Syndrome report of eight additional cases and review
American Journal of Medical Genetics, 2001Co-Authors: Ernie M.h.f. Bongers, Raoul C.m. Hennekam, Pierre Sarda, John M Opitz, Alan Fryer, Bryan D Hall, Duane W Superneau, M Harbison, A Poss, H Van BokhovenAbstract:The Meier-Gorlin Syndrome or ear, patella, short stature Syndrome (MIM 224690) is a rare autosomal recessive disorder, characterized by the association of bilateral microtia, aplasia/hypoplasia of the patellae, and severe pre- and postnatal growth retardation. Twenty-one cases have been reported in literature thus far. Here we report on eight patients from seven families and compare them with previously described cases. One of the present cases had previously undescribed genital anomalies. There is a difference in facial characteristics between patients reported in early infancy and those described at older age; follow-up of patients is needed to substantiate this changing facial phenotype. We recommend radiographic survey of the patellae in patients at older age to investigate the weight of absent or hypoplastic patellae in the diagnosis of the Syndrome.
Jikui Song - One of the best experts on this subject based on the ideXlab platform.
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ORC1 BAH domain links H4K20me2 to DNA replication licensing and Meier-Gorlin Syndrome
2016Co-Authors: Alex J. Kuo, Jikui Song, Peggie Cheung, James K Chen, Dinshaw J Patel, Satoko Ishibe-murakami, Or GozaniAbstract:Recognition of distinctly modified histones by specialized “effector ” proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes1. Effector proteins influence DNA-templated processes, including transcription, DNA recombination, and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulates DNA replication. Here we show that ORC1 – a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing2 – contains a BAH (bromo adjacent homology) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyllysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at origins, ORC chromatin loading, and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the etiology of Meier-Gorlin Syndrome (MGS)3,4, a form of primordial dwarfism5, and ORC1 depletion in zebrafish results in an MGS-like phenotype4. We find that wild-type human ORC1, but not ORC1 H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyllysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal etiologic role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism
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A Meier-Gorlin Syndrome Mutation Impairs the ORC1-Nucleosome Association
ACS chemical biology, 2015Co-Authors: Wei Zhang, Or Gozani, Saumya M. Sankaran, Jikui SongAbstract:Recent studies have identified several genetic mutations within the BAH domain of human Origin Recognition Complex subunit 1 (hORC1BAH), including the R105Q mutation, implicated in Meier-Gorlin Syndrome (MGS). However, the pathological role of the hORC1 R105Q mutation remains unclear. In this study, we have investigated the interactions of the hORC1BAH domain with histone H4K20me2, DNA, and the nucleosome core particle labeled with H4Kc20me2, a chemical analog of H4K20me2. Our study revealed a nucleosomal DNA binding site for hORC1BAH. The R105Q mutation reduces the hORC1BAH-DNA binding affinity, leading to impaired hORC1BAH-nucleosome interaction, which likely influences DNA replication initiation and MGS pathogenesis. This study provides an etiologic link between the hORC1 R105Q mutation and MGS.
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A Meier-Gorlin Syndrome Mutation Impairs the ORC1-Nucleosome Association
2015Co-Authors: Wei Zhang, Or Gozani, Saumya Sankaran, Jikui SongAbstract:Recent studies have identified several genetic mutations within the BAH domain of human Origin Recognition Complex subunit 1 (hORC1BAH), including the R105Q mutation, implicated in Meier-Gorlin Syndrome (MGS). However, the pathological role of the hORC1 R105Q mutation remains unclear. In this study, we have investigated the interactions of the hORC1BAH domain with histone H4K20me2, DNA, and the nucleosome core particle labeled with H4Kc20me2, a chemical analog of H4K20me2. Our study revealed a nucleosomal DNA binding site for hORC1BAH. The R105Q mutation reduces the hORC1BAH–DNA binding affinity, leading to impaired hORC1BAH–nucleosome interaction, which likely influences DNA replication initiation and MGS pathogenesis. This study provides an etiologic link between the hORC1 R105Q mutation and MGS
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the bah domain of orc1 links h4k20me2 to dna replication licensing and meier Gorlin Syndrome
Nature, 2012Co-Authors: Jikui Song, Peggie Cheung, Satoko Ishibemurakami, Sayumi Yamazoe, James K Chen, Dinshaw J Patel, Or GozaniAbstract:The ORC1 BAH domain is shown to be a module that recognizes a histone modification associated with replication origins, providing insight into the aetiology of Meier–Gorlin Syndrome. ORC1 is a subunit of the replication-licensing machinery that associates with replication origins, and mutations in the ORC1 BAH domain have been associated with a dwarfism Syndrome. Here, the ORC1 BAH domain is shown to comprise a module that recognizes a histone modification associated with replication origins. Insight into the molecular basis of the interaction is provided by a crystal structure. The interaction between ORC1 BAH domain and the histone modification is required for loading of ORC onto chromatin, and is also required to prevent dwarfism in a zebrafish model of the disease. The recognition of distinctly modified histones by specialized ‘effector’ proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes1. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1—a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing2—contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier–Gorlin Syndrome (MGS)3,4, a form of primordial dwarfism5, and ORC1 depletion in zebrafish results in an MGS-like phenotype4. We find that wild-type human ORC1, but not ORC1–H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.
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the bah domain of orc1 links h4k20me2 to dna replication licensing and meier Gorlin Syndrome
Nature, 2012Co-Authors: Alex J. Kuo, Jikui Song, Peggie Cheung, Satoko Ishibemurakami, Sayumi Yamazoe, James K Chen, Dinshaw J Patel, Or GozaniAbstract:The recognition of distinctly modified histones by specialized 'effector' proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1--a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing--contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier-Gorlin Syndrome (MGS), a form of primordial dwarfism, and ORC1 depletion in zebrafish results in an MGS-like phenotype. We find that wild-type human ORC1, but not ORC1-H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.
Louise S. Bicknell - One of the best experts on this subject based on the ideXlab platform.
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successful pregnancies in an adult with meier Gorlin Syndrome harboring biallelic cdt1 variants
American Journal of Medical Genetics Part A, 2021Co-Authors: Karen M Knapp, Jennie E Murray, Karen I Temple, Louise S. BicknellAbstract:Meier-Gorlin Syndrome is an autosomal recessively inherited disorder of growth retardation, accompanied by microtia and patellae a/hypoplasia and characteristic facies. Pathogenic variants in genes associated with the initiation of DNA replication underlie the condition, with biallelic variants in CDT1 the most common cause. Using 10X Chromium genome sequencing, we report CDT1 variants in an adult female, with an inframe amino acid deletion inherited in trans with a deep intronic variant which likely serves as the branchpoint site in intron 8. Splicing defects arising from this variant were confirmed through in vitro analysis. At 49 years, she represents the oldest patient with a molecular diagnosis described in the literature and is the first reported patient with Meier-Gorlin Syndrome to have carried a successful pregnancy to term. Both of her pregnancies were complicated by postpartum haemorrhage and upon subsequent necessary hysterectomy, revealed uterine abnormalities. There is scant knowledge on reproductive ability and success in patients with Meier-Gorlin Syndrome. Successful pregnancies amongst other clinically recognisable forms of primordial dwarfism have also not been described previously. This case is therefore of clinical interest for many forms of inherited growth retardation, and will assist in providing more information and clinical guidance for females of reproductive age
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meier Gorlin Syndrome genotype phenotype studies
2016Co-Authors: Sonja A De Munnik, Louise S. Bicknell, Salim Aftimos, Michael B. Bober, Jumana Y Alaama, Yolande Van Bever, Jill Claytonsmith, Alaa Y Edrees, Murray Feingold, Alan FryerAbstract:Meier–Gorlin Syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype–phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months–47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42% predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype–phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed.
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meier Gorlin Syndrome growth and secondary sexual development of a microcephalic primordial dwarfism disorder
American Journal of Medical Genetics Part A, 2012Co-Authors: Sonja A De Munnik, Louise S. Bicknell, Jeroen Schoots, Salim Aftimos, Michael B. Bober, Barto J Otten, Jumana Y Alaama, Yolande Van Bever, George F Borm, Jill ClaytonsmithAbstract:Meier-Gorlin Syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth.
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mutations in orc1 encoding the largest subunit of the origin recognition complex cause microcephalic primordial dwarfism resembling meier Gorlin Syndrome
Nature Genetics, 2011Co-Authors: Louise S. Bicknell, Andrea Leitch, Sarah R Walker, Anna Klingseisen, Tom Stiff, Claudia Kerzendorfer, Carol Anne Martin, Patricia L Yeyati, Nouriya Al Sanna, Michael B. BoberAbstract:Studies into disorders of extreme growth failure (for example, Seckel Syndrome and Majewski osteodysplastic primordial dwarfism type II) have implicated fundamental cellular processes of DNA damage response signaling and centrosome function in the regulation of human growth. Here we report that mutations in ORC1, encoding a subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin Syndrome. We establish that these mutations disrupt known ORC1 functions including pre-replicative complex formation and origin activation. ORC1 deficiency perturbs S-phase entry and S-phase progression. Additionally, we show that Orc1 depletion in zebrafish is sufficient to markedly reduce body size during rapid embryonic growth. Our data suggest a model in which ORC1 mutations impair replication licensing, slowing cell cycle progression and consequently impeding growth during development, particularly at times of rapid proliferation. These findings establish a novel mechanism for the pathogenesis of microcephalic dwarfism and show a surprising but important developmental impact of impaired origin licensing.
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Mutations in the pre-replication complex cause Meier-Gorlin Syndrome
Nature genetics, 2011Co-Authors: Louise S. Bicknell, Ernie M.h.f. Bongers, Andrea Leitch, Stephen Brown, Jeroen Schoots, Margaret E. Harley, Salim Aftimos, Jumana Y. Al-aama, Michael B. Bober, Paul A.j. BrownAbstract:Meier-Gorlin Syndrome (ear, patella and short-stature Syndrome) is an autosomal recessive primordial dwarfism Syndrome characterized by absent or hypoplastic patellae and markedly small ears¹⁻³. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this Syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic Syndrome with distinct developmental abnormalities.
Or Gozani - One of the best experts on this subject based on the ideXlab platform.
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ORC1 BAH domain links H4K20me2 to DNA replication licensing and Meier-Gorlin Syndrome
2016Co-Authors: Alex J. Kuo, Jikui Song, Peggie Cheung, James K Chen, Dinshaw J Patel, Satoko Ishibe-murakami, Or GozaniAbstract:Recognition of distinctly modified histones by specialized “effector ” proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes1. Effector proteins influence DNA-templated processes, including transcription, DNA recombination, and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulates DNA replication. Here we show that ORC1 – a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing2 – contains a BAH (bromo adjacent homology) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyllysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at origins, ORC chromatin loading, and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the etiology of Meier-Gorlin Syndrome (MGS)3,4, a form of primordial dwarfism5, and ORC1 depletion in zebrafish results in an MGS-like phenotype4. We find that wild-type human ORC1, but not ORC1 H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyllysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal etiologic role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism
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A Meier-Gorlin Syndrome Mutation Impairs the ORC1-Nucleosome Association
ACS chemical biology, 2015Co-Authors: Wei Zhang, Or Gozani, Saumya M. Sankaran, Jikui SongAbstract:Recent studies have identified several genetic mutations within the BAH domain of human Origin Recognition Complex subunit 1 (hORC1BAH), including the R105Q mutation, implicated in Meier-Gorlin Syndrome (MGS). However, the pathological role of the hORC1 R105Q mutation remains unclear. In this study, we have investigated the interactions of the hORC1BAH domain with histone H4K20me2, DNA, and the nucleosome core particle labeled with H4Kc20me2, a chemical analog of H4K20me2. Our study revealed a nucleosomal DNA binding site for hORC1BAH. The R105Q mutation reduces the hORC1BAH-DNA binding affinity, leading to impaired hORC1BAH-nucleosome interaction, which likely influences DNA replication initiation and MGS pathogenesis. This study provides an etiologic link between the hORC1 R105Q mutation and MGS.
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A Meier-Gorlin Syndrome Mutation Impairs the ORC1-Nucleosome Association
2015Co-Authors: Wei Zhang, Or Gozani, Saumya Sankaran, Jikui SongAbstract:Recent studies have identified several genetic mutations within the BAH domain of human Origin Recognition Complex subunit 1 (hORC1BAH), including the R105Q mutation, implicated in Meier-Gorlin Syndrome (MGS). However, the pathological role of the hORC1 R105Q mutation remains unclear. In this study, we have investigated the interactions of the hORC1BAH domain with histone H4K20me2, DNA, and the nucleosome core particle labeled with H4Kc20me2, a chemical analog of H4K20me2. Our study revealed a nucleosomal DNA binding site for hORC1BAH. The R105Q mutation reduces the hORC1BAH–DNA binding affinity, leading to impaired hORC1BAH–nucleosome interaction, which likely influences DNA replication initiation and MGS pathogenesis. This study provides an etiologic link between the hORC1 R105Q mutation and MGS
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the bah domain of orc1 links h4k20me2 to dna replication licensing and meier Gorlin Syndrome
Nature, 2012Co-Authors: Jikui Song, Peggie Cheung, Satoko Ishibemurakami, Sayumi Yamazoe, James K Chen, Dinshaw J Patel, Or GozaniAbstract:The ORC1 BAH domain is shown to be a module that recognizes a histone modification associated with replication origins, providing insight into the aetiology of Meier–Gorlin Syndrome. ORC1 is a subunit of the replication-licensing machinery that associates with replication origins, and mutations in the ORC1 BAH domain have been associated with a dwarfism Syndrome. Here, the ORC1 BAH domain is shown to comprise a module that recognizes a histone modification associated with replication origins. Insight into the molecular basis of the interaction is provided by a crystal structure. The interaction between ORC1 BAH domain and the histone modification is required for loading of ORC onto chromatin, and is also required to prevent dwarfism in a zebrafish model of the disease. The recognition of distinctly modified histones by specialized ‘effector’ proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes1. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1—a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing2—contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier–Gorlin Syndrome (MGS)3,4, a form of primordial dwarfism5, and ORC1 depletion in zebrafish results in an MGS-like phenotype4. We find that wild-type human ORC1, but not ORC1–H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.
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the bah domain of orc1 links h4k20me2 to dna replication licensing and meier Gorlin Syndrome
Nature, 2012Co-Authors: Alex J. Kuo, Jikui Song, Peggie Cheung, Satoko Ishibemurakami, Sayumi Yamazoe, James K Chen, Dinshaw J Patel, Or GozaniAbstract:The recognition of distinctly modified histones by specialized 'effector' proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1--a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing--contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier-Gorlin Syndrome (MGS), a form of primordial dwarfism, and ORC1 depletion in zebrafish results in an MGS-like phenotype. We find that wild-type human ORC1, but not ORC1-H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.
Matthias Brandis - One of the best experts on this subject based on the ideXlab platform.
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Focal dermal hypoplasia (Goltz-Gorlin Syndrome) associated with obstructive papillomatosis of the larynx and hypopharynx
European Journal of Dermatology, 1999Co-Authors: Nader Gordjani, S. Herdeg, U H Ross, Hi Grimme, Malte Kleinschmidt, Matthias BrandisAbstract:A 14-year-old girl with focal dermal hypoplasia (Goltz-Gorlin-Syndrome) presented with dysphagia, hoarseness, inspiratory stridor, intermittent dry cough and a 10% weight loss. Endoscopy showed that these symptoms were caused by papillomatosis of the hypopharynx and the larynx. The papillomatous masses were resected subtotally by endoscopic laser treatment. Residual papillomas were left in the subglottic space but tracheotomy could be avoided. Complete clinical recovery with adequate weight gain as well as, resolution of dyspnoe and dysphagia resulted after the intervention. Histological examination did not show morphological signs of human papilloma virus as an etiological agent.
