A case of autism spectrum disorder arising from a de novo missense mutation in POGZ

Fukai, Ryoko; Hiraki, Yoko; Yofune, Hiroko; Tsurusaki, Yoshinori; Nakashima, Mitsuko; Saitsu, Hirotomo; Tanaka, Fumiaki; Miyake, Noriko; Matsumoto, Naomichi

doi:10.1038/jhg.2015.13

Cited by 42 publications

(47 citation statements)

References 20 publications

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“…On the other hand, WES of affected and unaffected individuals has proven to be a powerful approach and has already led to the identification of more than 150 novel candidate genes for ASD . Compared to GWAS, WES provides new opportunities for sporadic cases and has the capacity to detect de novo mutations and variations with incomplete penetrance.…”

Section: Research Approachesmentioning

confidence: 99%

Autism genetics – an overview

Yin

Schaaf

2016

Prenatal Diagnosis

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Autism spectrum disorder (ASD) is a highly heritable, clinically diverse group of neurodevelopmental disorders. Its genetic heterogeneity is remarkable, with more than 800 ASD predisposition genes identified to date. They are involved in various biological processes, including chromatin remodeling and gene transcription regulation, cell growth and proliferation, ubiquitination, and neuronal-specific processes, such as synaptic organization and activity, dendritic morphology, and axonogenesis. This review aims to discuss basic autism genetics, explicate ways to investigate ASD in model systems, highlight some key genes and their molecular pathways, and introduce novel theories of ASD pathogenesis, such as imbalance of excitatory and inhibitory brain activity, oligogenic heterozygosity, and the female protective model. © 2016 John Wiley & Sons, Ltd.

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Section: Research Approachesmentioning

confidence: 99%

Autism genetics – an overview

Yin

Schaaf

2016

Prenatal Diagnosis

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“…For Patient 1, whole-exome sequencing (WES) was performed as previously described (Fukai et al, 2015). In brief, approximately 3 g DNA was sheared and used for a SureSelect Human All Exon V5 library (Agilent Technologies, Santa Clara, CA) For all patients, informed consent was obtained for the use of the data and photographs according to relevant institutional and national guidelines and regulations.…”

Section: Whole-exome Sequencingmentioning

confidence: 99%

Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders

et al. 2017

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The closely related paralogues FOXP2 and FOXP1 encode transcription factors with shared functions in the development of many tissues, including the brain. However, while mutations in FOXP2 lead to a speech/language disorder characterized by childhood apraxia of speech (CAS), the clinical profile of FOXP1 variants includes a broader neurodevelopmental phenotype with global developmental delay, intellectual disability, and speech/language impairment. Using clinical whole-exome sequencing, we report an identical de novo missense FOXP1 variant identified in three unrelated patients. The variant, p.R514H, is located in the forkhead-box DNA-binding domain and is equivalent to the well-studied p.R553H FOXP2 variant that cosegregates with CAS in a large UK family. We present here for the first time a direct comparison of the molecular and clinical consequences of the same mutation affecting the equivalent residue in FOXP1 and FOXP2. Detailed functional characterization of the two variants in cell model systems revealed very similar molecular consequences, including aberrant subcellular localization, disruption of transcription factor activity, and deleterious effects on protein interactions. Nonetheless, clinical manifestations were broader and more severe in the three cases carrying the p.R514H FOXP1 variant than in individuals with the p.R553H variant related to CAS, highlighting divergent roles of FOXP2 and FOXP1 in neurodevelopment.

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“…Many of the individuals with POGZ mutations have developmental delay, and more than half are diagnosed with ASD. Other phenotypes are intellectual disability, microcephaly, overly friendly behavior, short stature, hyperactivity and vision problems [16][17][18] . The disorder caused by POGZ mutations is now known as White-Sutton syndrome [MIM: 616364].…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, we noted that several of the high-confidence ASD risk genes are involved in heterochromatin formation or participate in complexes that bind different isotypes of the human heterochromatin protein 1 (HP1) (e.g. SUV420H1 12 , ADNP 13 and POGZ [14][15][16][17][18]. A key role of HP1 proteins is transcriptional silencing and modulation of chromatin architecture, including transcriptional repression of euchromatic genes 19 .…”

Section: Introductionmentioning

confidence: 99%

“…Not only is Pogz one of the most significantly associated genes with ASD, it is also consistently found to be a strong interactor with the three isotypes of HP1 [22][23][24] . Recent studies provided compelling evidence that loss-of-function (LoF) mutations in POGZ are associated with abnormal development and behavior [14][15][16][17][18] . Many of the individuals with POGZ mutations have developmental delay, and more than half are diagnosed with ASD.…”

Section: Introductionmentioning

confidence: 99%

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Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology

Suliman

Title

Cohen

et al. 2018

Preprint

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Genes implicated in autism spectrum disorder (ASD) are enriched with chromatin regulators, but the mechanisms leading to the abnormal behavior and cognition are still unclear. Animal models are crucial for studying the effects of mutations on brain function and behavior. We generated conditional knockout mice with brain-specific mutation in Pogz, a heterochromatin regulator recurrently mutated in ASD and other neurodevelopmental disorders, and demonstrated that these mice display phenotypes that resemble the human condition. Pogz deficiency led to smaller brain, growth impairment, motor learning deficits, and increased social interactions that mimic the human overly friendly phenotype. At the molecular level, reporter assay indicated that POGZ functions as a negative regulator of transcription through its interaction with HP1 proteins. In accordance, we found a significant upregulation of gene expression, most notably in the cerebellum. Furthermore, Pogz deficiency was associated with a significant reduction in the firing frequency of simple and complex spikes in cerebellar Purkinje cells with no changes in their intrinsic properties. Overall, our findings support a mechanism linking heterochromatin dysregulation to cerebellar circuit dysfunction and to motor and social abnormalities in ASD.

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A case of autism spectrum disorder arising from a de novo missense mutation in POGZ

Cited by 42 publications

References 20 publications

Autism genetics – an overview

Autism genetics – an overview

Equivalent missense variant in the FOXP2 and FOXP1 transcription factors causes distinct neurodevelopmental disorders

Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology

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