Katherine A Rauen

University of California, Davis, Davis, California, United States

Are you Katherine A Rauen?

Claim your profile

Publications (83)384.11 Total impact

  • Source

    Preview · Article · Jan 2016 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: RASopathies are developmental disorders caused by germline mutations in the Ras-MAPK pathway, and are characterized by a broad spectrum of functional and morphological abnormalities. The high incidence of these disorders (∼1/1000 births) motivates the development of systematic approaches for their efficient diagnosis and potential treatment. Recent advances in genome sequencing have greatly facilitated the genotyping and discovery of mutations in affected individuals, but establishing the causal relationships between molecules and disease phenotypes is non-trivial and presents both technical and conceptual challenges. Here, we discuss how these challenges could be addressed using genetically modified model organisms that have been instrumental in delineating the Ras-MAPK pathway and its roles during development. Focusing on studies in mice, zebrafish and Drosophila, we provide an up-to-date review of animal models of RASopathies at the molecular and functional level. We also discuss how increasingly sophisticated techniques of genetic engineering can be used to rigorously connect changes in specific components of the Ras-MAPK pathway with observed functional and morphological phenotypes. Establishing these connections is essential for advancing our understanding of RASopathies and for devising rational strategies for their management and treatment. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Aug 2015 · Disease Models and Mechanisms
  • Source

    Full-text · Dataset · Jun 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Astrocytes produce an assortment of signals that promote neuronal maturation according to a precise developmental timeline. Is this orchestrated timing and signaling altered in human neurodevelopmental disorders? To address this question, the astroglial lineage was investigated in two model systems of a developmental disorder with intellectual disability caused by mutant Harvey rat sarcoma viral oncogene homolog (HRAS) termed Costello syndrome: mutant HRAS human induced pluripotent stem cells (iPSCs) and transgenic mice. Human iPSCs derived from patients with Costello syndrome differentiated to astroglia more rapidly in vitro than those derived from wild-type cell lines with normal HRAS, exhibited hyperplasia, and also generated an abundance of extracellular matrix remodeling factors and proteoglycans. Acute treatment with a farnesyl transferase inhibitor and knockdown of the transcription factor SNAI2 reduced expression of several proteoglycans in Costello syndrome iPSC-derived astrocytes. Similarly, mice in which mutant HRAS was expressed selectively in astrocytes exhibited experience-independent increased accumulation of perineuronal net proteoglycans in cortex, as well as increased parvalbumin expression in interneurons, when compared to wild-type mice. Our data indicate that astrocytes expressing mutant HRAS dysregulate cortical maturation during development as shown by abnormal extracellular matrix remodeling and implicate excessive astrocyte-to-neuron signaling as a possible drug target for treating mental impairment and enhancing neuroplasticity. Copyright © 2015, American Association for the Advancement of Science.
    No preview · Article · May 2015 · Science translational medicine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: "The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach" was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Apr 2015 · American Journal of Medical Genetics Part A
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurofibromatosis type 1 (NF1) was the first RASopathy and is now one of many RASopathies that are caused by germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Their common underlying pathogenetic etiology causes significant overlap in phenotypic features which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium "Recent Developments in Neurofibromatoses (NF) and RASopathies: Management, Diagnosis and Current and Future Therapeutic Avenues" chronicle this timely and topical clinical translational research symposium. The overarching goal was to bring together clinicians, basic scientists, physician-scientists, advocate leaders, trainees, students and individuals with Ras pathway syndromes to discuss the most state-of-the-art basic science and clinical issues in an effort to spark collaborations directed towards the best practices and therapies for individuals with RASopathies. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Jan 2015 · American Journal of Medical Genetics Part A
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardio-facio-cutaneous syndrome (CFC) is one of the RASopathies that bears many clinical features in common with the other syndromes in this group, most notably Noonan syndrome and Costello syndrome. CFC is genetically heterogeneous and caused by gene mutations in the Ras/mitogen-activated protein kinase pathway. The major features of CFC include characteristic craniofacial dysmorphology, congenital heart disease, dermatologic abnormalities, growth retardation, and intellectual disability. It is essential that this condition be differentiated from other RASopathies, as a correct diagnosis is important for appropriate medical management and determining recurrence risk. Children and adults with CFC require multidisciplinary care from specialists, and the need for comprehensive management has been apparent to families and health care professionals caring for affected individuals. To address this need, CFC International, a nonprofit family support organization that provides a forum for information, support, and facilitation of research in basic medical and social issues affecting individuals with CFC, organized a consensus conference. Experts in multiple medical specialties provided clinical management guidelines for pediatricians and other care providers. These guidelines will assist in an accurate diagnosis of individuals with CFC, provide best practice recommendations, and facilitate long-term medical care.
    Full-text · Article · Sep 2014 · Pediatrics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Jun 2014 · American Journal of Medical Genetics Part A
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Constitutional SMARCB1 mutations at 22q11.23 have been found in ∼50% of familial and <10% of sporadic schwannomatosis cases. We sequenced highly conserved regions along 22q from eight individuals with schwannomatosis whose schwannomas involved somatic loss of one copy of 22q, encompassing SMARCB1 and NF2, with a different somatic mutation of the other NF2 allele in every schwannoma but no mutation of the remaining SMARCB1 allele in blood and tumor samples. LZTR1 germline mutations were identified in seven of the eight cases. LZTR1 sequencing in 12 further cases with the same molecular signature identified 9 additional germline mutations. Loss of heterozygosity with retention of an LZTR1 mutation was present in all 25 schwannomas studied. Mutations segregated with disease in all available affected first-degree relatives, although four asymptomatic parents also carried an LZTR1 mutation. Our findings identify LZTR1 as a gene predisposing to an autosomal dominant inherited disorder of multiple schwannomas in ∼80% of 22q-related schwannomatosis cases lacking mutation in SMARCB1.
    Full-text · Article · Dec 2013 · Nature Genetics
  • Jefferson Terry · Katherine A Rauen · Malgorzata J M Nowaczyk
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Cardiofaciocutaneous (CFC) syndrome is a RASopathy phenotypically characterized by facial, cardiac, and ectodermal abnormalities. The extent to which this phenotype is expressed in the affected fetus is unclear and a better understanding of the fetal autopsy findings in CFC syndrome could facilitate diagnosis and understanding of the developmental effects of dysregulated BRAF activity. Here we describe the fetal autopsy findings in case of CFC syndrome in a 17 week fetus with a novel BRAF mutation that demonstrate potential similarities and differences with the postnatal presentation of CFC syndrome.
    No preview · Article · Dec 2013 · Pediatric and Developmental Pathology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs. We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS). Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs. Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.
    Full-text · Article · Oct 2013 · Journal of Medical Genetics
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: RASopathies are syndromes caused by gain-of-function mutations in the Ras signaling pathway. One of these conditions, Costello syndrome (CS), is typically caused by an activating de novo germline mutation in HRAS and is characterized by a wide range of cardiac, musculoskeletal, dermatological and developmental abnormalities. We report that a majority of individuals with CS have hypo-mineralization of enamel, the outer covering of teeth, and that similar defects are present in a CS mouse model. Comprehensive analysis of the mouse model revealed that ameloblasts, the cells that generate enamel, lacked polarity, and the ameloblast progenitor cells were hyperproliferative. Ras signals through two main effector cascades, the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways. To determine through which pathway Ras affects enamel formation, inhibitors targeting either PI3K or MEK 1 and 2 (MEK 1/2), kinases in the MAPK pathway, were utilized. MEK1/2 inhibition rescued the hypo-mineralized enamel, normalized the ameloblast polarity defect and restored normal progenitor cell proliferation. In contrast, PI3K inhibition only corrected the progenitor cell proliferation phenotype. We demonstrate for the first time the central role of Ras signaling in enamel formation in CS individuals and present the mouse incisor as a model system to dissect the roles of the Ras effector pathways in vivo.
    Full-text · Article · Sep 2013 · Human Molecular Genetics
  • William E. Tidyman · Katherine A. Rauen
    [Show abstract] [Hide abstract]
    ABSTRACT: A class of clinically related developmental disorders, the RASopathies, has recently been shown to be caused by germline mutations in genes that encode components, or regulators, of the Ras/mitogen-activated protein kinase (MAPK) pathway. Neurofibromatosis type 1, the first syndrome identified to be caused by a germline mutation in this pathway, was followed by other syndromes including Noonan, Noonan with multiple lentigines, capillary malformation-AV malformation, Costello, cardio-facio-cutaneous, and Legius. The Ras/MAPK pathway plays an essential role in the regulation of the cell cycle, differentiation, growth, and cell senescence, all of which are critical to normal development. As a result, Ras/MAPK pathway dysregulation has been shown to have profound deleterious effects on both embryonic and later stages of development. Because the underlying molecular mechanism for these syndromes is dysregulation of the Ras/MAPK pathway, the RASopathies exhibit numerous overlapping phenotypic features, including reduced growth, characteristic facial features, cardiac defects, cutaneous abnormalities, neurocognitive delay, and a predisposition to neoplasia, both benign and malignant. As a group, the RASopathies are one of the largest recognizable patterns of malformation syndromes known, affecting approximately 1:1,000 individuals. © 2012 Springer-Verlag Berlin Heidelberg. All rights are reserved.
    No preview · Article · Aug 2013
  • Source
    Katherine A Rauen
    [Show abstract] [Hide abstract]
    ABSTRACT: The RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 14 is August 31, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    Preview · Article · Jul 2013 · Annual review of genomics and human genetics
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: Receptor tyrosine kinase (RTK) signaling pathways are known to play a central role in tooth development. Costello Syndrome (CS), is caused by a heterozygous, de novo germline mutation in HRAS, which is downstream of RTK, that results in a constitutively active Ras protein. In order to further understand the role of Ras signaling in tooth development, we performed craniofacial and dental exams on a total of 46 patients with CS at the CS International Family Conferences in 2009 and 2011. Method: Exams included intra- and extraoral photographs, clinical examinations, x-ray reviews, alginate impressions, and exfoliated CS teeth collection. Result: Our dental exams revealed that patients with CS display malocclusion, delayed tooth development and delayed eruption. Interestingly, 88% of individuals with CS presented with an enamel defect characterized clinically by generalized white spots and striations. Micro computed tomography (microCT) and scanning electron microscopy (SEM) of exfoliated primary teeth from CS patients showed a significant decrease in enamel thickness and mineralization compared to control. Next, we analyzed a CS mouse model expressing HRASG12V in the lab and found that the CS mouse model has an enamel defect. Further inspection revealed disorganized enamel structure with demineralized zones. In addition, ameloblast progenitor cells were hyperproliferative in the cervical loop, and ameloblasts were disorganized and expressed decreased levels of enamel matrix proteins. Currently, we are analyzing HRASG12V mice treated with inhibitors at multiple points along the Ras effector pathways in order to determine through which pathway Ras is affecting ameloblast proliferation and differentiation and enamel formation. Conclusion: CS individuals present with a distinct craniofacial and dental phenotype, including an enamel defect. Our study in the CS mouse suggests that ameloblast proliferation and differentiation is disrupted resulting in the enamel defect, revealing an important role for Ras signaling in amelogenesis.
    No preview · Conference Paper · Mar 2013
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report an 8-month-old boy with Emanuel syndrome who also had the clinical features of Goldenhar syndrome. At birth, he was observed to have bilateral microtia with multiple auricular pits, retrognathia, and a unilateral lipodermoid. Further testing revealed cardiac defects. The finding of a lipodermoid in Emanuel syndrome demonstrates phenotypic overlap between Goldenhar and Emanuel syndromes and suggests a role for genetic analysis in all patients with clinical features that include ear anomalies and lipodermoids. Correct identification of patients with Emanuel syndrome is important for determining whether there is risk of long-term neurodevelopmental disability, and genetic testing can determine parental carrier status to aid in family planning.
    No preview · Article · Mar 2013 · Journal of AAPOS: the official publication of the American Association for Pediatric Ophthalmology and Strabismus / American Association for Pediatric Ophthalmology and Strabismus
  • [Show abstract] [Hide abstract]
    ABSTRACT: RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/MAPK pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, GE reflux and integument abnormalities. Analysis of EGF stimulated fibroblasts revealed that P-MEK1/2 was ~50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.
    No preview · Article · Feb 2013 · Clinical Genetics
  • [Show abstract] [Hide abstract]
    ABSTRACT: RASopathies are a group of genetic conditions due to alterations of the Ras/MAPK pathway. Neurocutaneous findings are hallmark features of the RASopathies, but musculoskeletal abnormalities are also frequent. The objective was to evaluate handgrip strength in the RASopathies. Individuals with RASopathies (e.g., Noonan syndrome, Costello syndrome, cardio-facio-cutaneous [CFC] syndrome, and neurofibromatosis type 1 [NF1]) and healthy controls were evaluated. Two methods of handgrip strength were tested: GRIP-D Takei Hand Grip Dynamometer and the Martin vigorimeter. A general linear model was fitted to compare average strength among the groups, controlling for confounders such as age, gender, height, and weight. Takei dynamometer: handgrip strength was decreased in each of the syndromes compared with controls. Decreased handgrip strength compared with sibling controls was also seen with the Martin vigorimeter (P < 0.0001). Handgrip strength is decreased in the RASopathies. The etiology of the reduced muscle force is unknown, but likely multifactorial.
    No preview · Article · Sep 2012 · Muscle & Nerve
  • Bing Huang · Phyllis Pearle · Katherine A Rauen · Philip D Cotter
    [Show abstract] [Hide abstract]
    ABSTRACT: Supernumerary marker chromosomes (SMC) are relatively common in prenatal diagnosis. As the clinical outcomes vary greatly, a better understanding of the karyotype-phenotype correlation for different SMCs will be important for genetic counseling. We present two cases of prenatally detected de novo, small SMCs. The markers were present in 80% of amniocyte colonies in Case 1 and 38% of the colonies in Case 2. The SMCs were determined to be derived from chromosome 6 during postnatal confirmation studies. Although the sizes and the chromosomal origin of the SMCs in these two cases appeared to be similar, the clinical outcomes varied. The clinical manifestations observed in Case 1 included small for gestational age, feeding difficulty at birth, hydronephrosis, deviated septum and dysmorphic features, while the phenotype is apparently normal in Case 2. Array comparative genomic hybridization (CGH) was performed and showed increase in dosage for approximately 26 Mb of genetic material from the proximal short and long arms of chromosome 6 in Case 1. Results of array CGH were uninformative in Case 2, either due to mosaicism or lack of detectable euchromatin. The difference in the clinical presentation in these two patients may have resulted from the difference in the actual gene contents of the marker chromosomes and/or the differential distribution of the mosaicism.
    No preview · Article · Jul 2012 · American Journal of Medical Genetics Part A
  • [Show abstract] [Hide abstract]
    ABSTRACT: A 16-year-old man with splenomegaly presented with ascites and bilateral leg eschars. Although he had intermittently elevated absolute monocyte counts, a diagnosis of juvenile myelomonocytic leukemia (JMML) was discounted because of his age and lack of persistent leukocytosis. Detailed examination demonstrated features consistent with Noonan syndrome (NS), including typical facies, growth retardation, a cardiac defect, and a history of a coagulopathy. He underwent a splenectomy where the surgeons encountered a rind of tissue composed of monocytes encasing the abdominal organs. After splenectomy, his leukocytes rose to over 100×10/L with a monocytosis, suggesting JMML. On the basis of the clinical suspicion of NS, mutation analysis revealed a KRAS mutation, which is known to be common to both NS and JMML. Clinicians should have high index of suspicion for JMML in patients with Noonan features, regardless of a patient's age.
    No preview · Article · Apr 2012 · Journal of Pediatric Hematology/Oncology

Publication Stats

3k Citations
384.11 Total Impact Points

Institutions

  • 2014-2015
    • University of California, Davis
      • Department of Pediatrics
      Davis, California, United States
  • 2000-2014
    • University of California, San Francisco
      • • Department of Pediatrics
      • • Division of Medical Genetics
      • • Division of Hospital Medicine
      San Francisco, California, United States
  • 2005
    • Baylor College of Medicine
      Houston, Texas, United States
  • 2002
    • Cancer Research Institute
      New York, New York, United States