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1.
Hum Mol Genet ; 25(3): 546-57, 2016 Feb 01.
Article in English | MEDLINE | ID: mdl-26647308

ABSTRACT

De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.


Subject(s)
Developmental Disabilities/genetics , Forkhead Transcription Factors/genetics , Hypertelorism/genetics , Intellectual Disability/genetics , Language Development Disorders/genetics , Mutation, Missense , Repressor Proteins/genetics , Adolescent , Base Sequence , Child , DNA/genetics , DNA/metabolism , Developmental Disabilities/metabolism , Developmental Disabilities/pathology , Exome , Female , Forkhead Transcription Factors/metabolism , Gene Expression Regulation , High-Throughput Nucleotide Sequencing , Humans , Hypertelorism/metabolism , Hypertelorism/pathology , Intellectual Disability/metabolism , Intellectual Disability/pathology , Language Development Disorders/metabolism , Language Development Disorders/pathology , Male , Molecular Sequence Data , Pedigree , Protein Binding , Repressor Proteins/metabolism , Signal Transduction , Transcription, Genetic
2.
N Engl J Med ; 372(7): 601-612, 2015 Feb 12.
Article in English | MEDLINE | ID: mdl-25671252

ABSTRACT

BACKGROUND: Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect the sum of these mutations. However, little is known about the effect of the order in which mutations are acquired. METHODS: We determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. RESULTS: The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 mutation was acquired first (hereafter referred to as "TET2-first patients"), patients in whom the Janus kinase 2 (JAK2) mutation was acquired first ("JAK2-first patients") had a greater likelihood of presenting with polycythemia vera than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from up-regulating genes associated with proliferation. CONCLUSIONS: The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. (Funded by Leukemia and Lymphoma Research and others.).


Subject(s)
DNA-Binding Proteins/genetics , Hematopoietic Stem Cells/physiology , Janus Kinase 2/genetics , Mutation , Myeloproliferative Disorders/genetics , Proto-Oncogene Proteins/genetics , Age of Onset , Cell Proliferation/genetics , DNA Mutational Analysis , Dioxygenases , Gene Expression , Homozygote , Humans , Polycythemia Vera/genetics , Thrombocythemia, Essential/genetics , Thrombosis/genetics , Transcription, Genetic , Up-Regulation
3.
Nat Commun ; 5: 4954, 2014 Sep 18.
Article in English | MEDLINE | ID: mdl-25232744

ABSTRACT

Next-generation sequencing recently revealed that recurrent disruptive mutations in a few genes may account for 1% of sporadic autism cases. Coupling these novel genetic data to empirical assays of protein function can illuminate crucial molecular networks. Here we demonstrate the power of the approach, performing the first functional analyses of TBR1 variants identified in sporadic autism. De novo truncating and missense mutations disrupt multiple aspects of TBR1 function, including subcellular localization, interactions with co-regulators and transcriptional repression. Missense mutations inherited from unaffected parents did not disturb function in our assays. We show that TBR1 homodimerizes, that it interacts with FOXP2, a transcription factor implicated in speech/language disorders, and that this interaction is disrupted by pathogenic mutations affecting either protein. These findings support the hypothesis that de novo mutations in sporadic autism have severe functional consequences. Moreover, they uncover neurogenetic mechanisms that bridge different neurodevelopmental disorders involving language deficits.


Subject(s)
Autism Spectrum Disorder/genetics , Mutation , T-Box Domain Proteins/genetics , Amino Acid Sequence , Cell Line, Tumor , Child , Child, Preschool , Dimerization , Female , Forkhead Transcription Factors/metabolism , HEK293 Cells , High-Throughput Nucleotide Sequencing , Humans , Language Disorders/genetics , Male , Molecular Sequence Data , Mutagenesis, Site-Directed , Mutation, Missense , Protein Interaction Mapping , Sequence Homology, Amino Acid , Two-Hybrid System Techniques
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