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Bicknell L.S.,Medical Research Council MRC | Walker S.,University of Sussex | Klingseisen A.,Medical Research Council MRC | Stiff T.,University of Sussex | And 11 more authors.
Nature Genetics | Year: 2011

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. © 2011 Nature America, Inc. All rights reserved.

Geusau A.,Medical University of Vienna | Mothes-Luksch N.,Medical University of Vienna | Nahavandi H.,Medical University of Vienna | Pickl W.F.,Institute of Immunology | And 2 more authors.
JAMA Dermatology | Year: 2013

Background: Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome (OMIM 604416) is a rare autosomal dominant inherited autoinflammatory syndrome characterized by pyogenic sterile arthritis and less frequently accompanied by pyoderma gangrenosum and acne. It is associated with dominant missense mutations in the proline-serine-threonine phosphatase- interacting protein 1 gene (PSTPIP1) located on chromosome 15. The patient was diagnosed as having features of a PAPA-like syndrome in which cutaneous manifestations, such as pyoderma gangrenosum and acne fulminans, predominated. Observations: Sequencing of the PSTPIP1 gene was performed in the patient and his extended family. The patient's DNA analysis revealed a homozygous nucleotide exchange c.773G>C in the PSTPIP1 gene, leading to the substitution of glycine 258 by alanine (p.Gly258Ala), a previously reported heterozygous polymorphism. Heterozygous changes were identified in both of the patient's parents and in 7 other family members, all of whom were asymptomatic. The patient was treated with canakinumab, a human anti-interleukin 1β monoclonal antibody, which led to rapid remission of the symptoms. Conclusions: To our knowledge, this is the first reported case of the resolution of dermatological symptoms associated with a PAPA-like syndrome using canakinumab treatment. Further study of the p.Gly258Ala variant is warranted to determine whether this mutation has a role in causing an apparently recessive cutaneous syndrome resembling PAPA syndrome. © 2013 American Medical Association. All rights reserved.

De La Croix Ndong J.,Vanderbilt University | Makowski A.J.,Vanderbilt University | Uppuganti S.,Vanderbilt University | Vignaux G.,Vanderbilt University | And 11 more authors.
Nature Medicine | Year: 2014

Individuals with neurofibromatosis type-1 (NF1) can manifest focal skeletal dysplasias that remain extremely difficult to treat. NF1 is caused by mutations in the NF1 gene, which encodes the RAS GTPase-activating protein neurofibromin. We report here that ablation of Nf1 in bone-forming cells leads to supraphysiologic accumulation of pyrophosphate (PP i), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal-regulated kinase (ERK)-dependent increase in expression of genes promoting PP i synthesis and extracellular transport, namely Enpp1 and Ank, causes this phenotype. Nf1 ablation also prevents bone morphogenic protein-2-induced osteoprogenitor differentiation and, consequently, expression of alkaline phosphatase and PP i breakdown, further contributing to PP i accumulation. The short stature and impaired bone mineralization and strength in mice lacking Nf1 in osteochondroprogenitors or osteoblasts can be corrected by asfotase- α enzyme therapy aimed at reducing PP i concentration. These results establish neurofibromin as an essential regulator of bone mineralization. They also suggest that altered PP i homeostasis contributes to the skeletal dysplasias associated with NF1 and that some of the NF1 skeletal conditions could be prevented pharmacologically. © 2014 Nature America, Inc.

Paria N.,Sarah d Charles ay Center For Musculoskeletal Research | Wise C.A.,Sarah d Charles ay Center For Musculoskeletal Research | Wise C.A.,University of Texas Southwestern Medical Center
Seminars in Spine Surgery | Year: 2015

Adolescent idiopathic scoliosis (AIS) is the most common pediatric musculoskeletal disorder, affecting about 2-3% of the children worldwide. The underlying etiology of AIS has proven elusive, in part due to the lack of appropriate animal models and systems that would enable laboratory-based research. In contrast, genetic studies in patient populations have highlighted several candidate genes suggesting possible neuromuscular origins. Developing genetically defined animal models to facilitate hypothesis testing is a high priority for ongoing AIS research. Continued gene discovery efforts supported by next-generation genomic platforms will yield exciting new insights into AIS disease pathways, opening the prospect for pharmaceutical interventions. © 2015 Elsevier Inc.

Rios J.J.,Sarah d Charles ay Center For Musculoskeletal Research | Rios J.J.,University of Texas Southwestern Medical Center | Delgado M.R.,Texas Scottish Rite Hospital for Children | Delgado M.R.,University of Texas Southwestern Medical Center
European Journal of Human Genetics | Year: 2015

Whole-exome sequencing (WES) has allowed the discovery of genes and variants causing rare human disease. This is often achieved by comparing nonsynonymous variants between unrelated patients, and particularly for sporadic or recessive disease, often identifies a single or few candidate genes for further consideration. However, despite the potential for this approach to elucidate the genetic cause of rare human disease, a majority of patients fail to realize a genetic diagnosis using standard exome analysis methods. Although genetic heterogeneity contributes to the difficulty of exome sequence analysis between patients, it remains plausible that rare human disease is not caused by de novo or recessive variants. Multiple human disorders have been described for which the variant was inherited from a phenotypically normal mosaic parent. Here we highlight the potential for exome sequencing to identify a reasonable number of candidate genes when dominant disease variants are inherited from a mosaic parent. We show the power of WES to identify a limited number of candidate genes using this disease model and how sequence coverage affects identification of mosaic variants by WES. We propose this analysis as an alternative to discover genetic causes of rare human disorders for which typical WES approaches fail to identify likely pathogenic variants. © 2015 Macmillan Publishers Limited All rights reserved.

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