Biological Significance of de novo mutations in autism spectrum disorder

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  • Nakazawa Takanobu
    Department of Pharmacology, Graduate School of Dentistry, Osaka University / Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University

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  • 自閉スペクトラム症に高頻度に認める<i>POGZ</i>遺伝子座の患者特異的<i>de novo</i>変異の表現型解析
  • 自閉スペクトラム症に高頻度に認めるPOGZ遺伝子座の患者特異的de novo変異の表現型解析
  • ジヘイスペクトラムショウ ニ コウヒンド ニ ミトメル POGZ イデンシザ ノ カンジャ トクイテキ de novo ヘンイ ノ ヒョウゲンガタ カイセキ

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Abstract

Autism spectrum disorder (ASD) is one of a neurodevelopmental disorder, characterized by impairments in social interactions, reduced verbal communication abilities, stereotyped repetitive behaviors and restricted interests. Genetic studies have identified candidate genetic variants, including SHANK3, NLGN3, NLGN4 and NRXN1. However, for about 70-90% of cases, the underlying molecular etiology remains unclear. Considering that most cases of ASD are sporadic, de novo mutations may contribute to a substantial fraction of the risk of ASD. Recently, genes with highly recurrent de novo possible loss-of-function mutations, including SCN2A, ANK2, SYNGAP1, ARID1B, CHD8, CHD2, SUV420H1, TBR1, ADNP, TRIP12, DYRK1, PTEN, DSCAM and POGZ have been identified in multiple unrelated patients. Among these high-confidence ASD risk genes, POGZ is one of the most recurrently mutated genes in ASD patients ; we and other groups have recently identified at least 20 independent de novo possible loss-of-function mutations in POGZ. However, the biological significance of these mutations as well as the precise role of POGZ in the brain remains unknown. To examine the significance of the Q1042R mutation in the risk for developing ASD, we established iPS cells from the patient who has the Q1042R mutation. We preliminarily found that POGZ is involved in the neuronal differentiation, providing important insights into the cellular basis of ASD.

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