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Michael B Bober - One of the best experts on this subject based on the ideXlab platform.
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microcephalic osteodysplastic primordial Dwarfism type ii a clinical review
Current Osteoporosis Reports, 2017Co-Authors: Michael B Bober, Andrew P JacksonAbstract:This review will provide an overview of the microcephalic primordial Dwarfism (MPD) class of disorders and provide the reader comprehensive clinical review with suggested care guidelines for patients with microcephalic osteodysplastic primordial Dwarfism, type II (MOPDII). Over the last 15 years, significant strides have been made in the diagnosis, natural history, and management of MOPDII. MOPDII is the most common and well described form of MPD. The classic features of the MPD group are severe pre- and postnatal growth retardation, with marked microcephaly. In addition to these features, individuals with MOPDII have characteristic facies, skeletal dysplasia, abnormal dentition, and an increased risk for cerebrovascular disease and insulin resistance. Biallelic loss-of-function mutations in the pericentrin gene cause MOPDII, which is inherited in an autosomal recessive manner.
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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, Sarah R Walker, Anna Klingseisen, Tom Stiff, Andrea Leitch, 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.
Khalda Amr - One of the best experts on this subject based on the ideXlab platform.
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Expanding the phenotypic and mutational spectrum in microcephalic osteodysplastic primordial Dwarfism type I.
American journal of medical genetics. Part A, 2012Co-Authors: Ghada M H Abdel-salam, Mohamed S Abdel-hamid, Mahmoud Issa, Ahmed Magdy, Ahmed El-kotoury, Khalda AmrAbstract:Mutations in the RNU4ATAC gene cause microcephalic osteodysplastic primordial Dwarfism type I. It encodes U4atac, a small nuclear RNA that is a component of the minor spliceosome. Six distinct mutations in 30 patients diagnosed as microcephalic osteodysplastic primordial Dwarfism type I have been described. We report on three additional patients from two unrelated families presenting with a milder phenotype of microcephalic osteodysplastic primordial Dwarfism type I and metopic synostosis. Patient 1 had two novel heterozygous mutations in the 3' prime stem-loop, g.66G > C and g.124G > A while Patients 2 and 3 had a homozygous mutation g.55G > A in the 5' prime stem-loop. Although they manifested the known spectrum of clinical features of microcephalic osteodysplastic primordial Dwarfism type I, they lacked evidence of severe developmental delay and neurological symptoms. These findings expand the mutational and phenotypic spectrum of this syndrome.
Hans S. Kooistra - One of the best experts on this subject based on the ideXlab platform.
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pituitary Dwarfism in saarloos and czechoslovakian wolfdogs is associated with a mutation in lhx3
Journal of Veterinary Internal Medicine, 2014Co-Authors: Annemarie M W Y Voorbij, Peter A.j. Leegwater, Hans S. KooistraAbstract:Background Pituitary Dwarfism in German Shepherd Dogs is associated with autosomal recessive inheritance and a mutation in LHX3, resulting in combined pituitary hormone deficiency. Congenital Dwarfism also is encountered in breeds related to German Shepherd Dogs, such as Saarloos and Czechoslovakian wolfdogs. Objectives To investigate whether Saarloos and Czechoslovakian wolfdog dwarfs have the same LHX3 mutation as do Germans Shepherd Dog dwarfs. A specific aim was to determine the carrier frequency among Saarloos and Czechoslovakian wolfdogs used for breeding. Animals Two client-owned Saarloos wolfdogs and 4 client-owned Czechoslovakian wolfdogs with pituitary Dwarfism, 239 clinically healthy client-owned Saarloos wolfdogs, and 200 client-owned clinically healthy Czechoslovakian wolfdogs. Methods Genomic DNA was amplified using polymerase chain reaction (PCR). In the Saarloos and Czechoslovakian wolfdog dwarfs, PCR products were analyzed by sequencing. DNA fragment length analysis was performed on the samples from the clinically healthy dogs. Results Saarloos and Czechoslovakian wolfdog dwarfs have the same 7 bp deletion in intron 5 of LHX3 as do German Shepherd Dog dwarfs. The frequency of carriers of this mutation among clinically healthy Saarloos and Czechoslovakian wolfdogs used for breeding was 31% and 21%, respectively. Conclusions and Clinical Importance An LHX3 mutation is associated with pituitary Dwarfism in Saarloos and Czechoslovakian wolfdogs. The rather high frequency of carriers of the mutated gene in the 2 breeds emphasizes the need for screening before breeding. If all breeding animals were genetically tested for the presence of the LHX3 mutation and a correct breeding policy would be implemented, this disease could be eradicated completely.
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the leukemia inhibitory factor receptor gene is not involved in the etiology of pituitary Dwarfism in german shepherd dogs
Research in Veterinary Science, 2006Co-Authors: J M Hanson, Peter A.j. Leegwater, Hans S. Kooistra, Björn P. MeijAbstract:Abstract Pituitary Dwarfism in German shepherd dogs is characterized by combined pituitary hormone deficiency (CPHD) and intrapituitary cyst formation. Activation of the leukemia inhibitory factor (LIF)–LIF receptor (LIFR) signal transduction pathway results in a similar phenotype in (transgenic) mice. We therefore assessed the role of the LIFR in the etiology of pituitary Dwarfism in German shepherd dogs. A polymorphic microsatellite marker (UULIFR) was used to analyze the segregation of the LIFR gene in 22 German shepherd dogs from 4 pedigrees, each including one dwarf. There was no allelic association between UULIFR and the Dwarfism phenotype. Based on our findings LIFR was excluded as a candidate gene for CPHD.
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exclusion of the lim homeodomain gene lhx4 as a candidate gene for pituitary Dwarfism in german shepherd dogs
Molecular and Cellular Endocrinology, 2002Co-Authors: Bernard A Van Oost, Sandra Imholz, Serge A Versteeg, Hans S. KooistraAbstract:Pituitary Dwarfism in the German shepherd dog is an autosomal recessive inherited abnormality. We tested the hypothesis that a variant of the LIM homeodomain gene LHX4 is responsible for the Dwarfism phenotype. To this end, we isolated Bacterial Artificial Chromosome clones for the canine LHX4 gene. Southern blotting experiments showed that the LHX4 gene is a single copy gene in the canine genome. A complex CA-repeat was isolated from the BAC clones and was found to be polymorphic in German shepherd dogs. Genotyping 5 litters in which the Dwarfism was segregating showed disconcordance between the inheritance of the Dwarfism phenotype and the DNA marker. It is concluded that the LHX4 gene does not play a primary role in the pituitary Dwarfism in the German shepherd dogs.
Andrew P Jackson - One of the best experts on this subject based on the ideXlab platform.
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microcephalic osteodysplastic primordial Dwarfism type ii a clinical review
Current Osteoporosis Reports, 2017Co-Authors: Michael B Bober, Andrew P JacksonAbstract:This review will provide an overview of the microcephalic primordial Dwarfism (MPD) class of disorders and provide the reader comprehensive clinical review with suggested care guidelines for patients with microcephalic osteodysplastic primordial Dwarfism, type II (MOPDII). Over the last 15 years, significant strides have been made in the diagnosis, natural history, and management of MOPDII. MOPDII is the most common and well described form of MPD. The classic features of the MPD group are severe pre- and postnatal growth retardation, with marked microcephaly. In addition to these features, individuals with MOPDII have characteristic facies, skeletal dysplasia, abnormal dentition, and an increased risk for cerebrovascular disease and insulin resistance. Biallelic loss-of-function mutations in the pericentrin gene cause MOPDII, which is inherited in an autosomal recessive manner.
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mechanisms and pathways of growth failure in primordial Dwarfism
Genes & Development, 2011Co-Authors: Anna Klingseisen, Andrew P JacksonAbstract:The greatest difference between species is size; however, the developmental mechanisms determining organism growth remain poorly understood. Primordial Dwarfism is a group of human single-gene disorders with extreme global growth failure (which includes Seckel syndrome, microcephalic osteodysplastic primordial Dwarfism I [MOPD] types I and II, and Meier-Gorlin syndrome). Ten genes have now been identified for microcephalic primordial Dwarfism, encoding proteins involved in fundamental cellular processes including genome replication (ORC1 [origin recognition complex 1], ORC4, ORC6, CDT1, and CDC6), DNA damage response (ATR [ataxia-telangiectasia and Rad3-related]), mRNA splicing (U4atac), and centrosome function (CEP152, PCNT, and CPAP). Here, we review the cellular and developmental mechanisms underlying the pathogenesis of these conditions and address whether further study of these genes could provide novel insight into the physiological regulation of organism growth.
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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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.
