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首页> 外文期刊>Human mutation >Alu‐Alu Alu‐Alu mediated intragenic duplications in IFT81 IFT81 and MATN3 MATN3 are associated with skeletal dysplasias
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Alu‐Alu Alu‐Alu mediated intragenic duplications in IFT81 IFT81 and MATN3 MATN3 are associated with skeletal dysplasias

机译：Alu-Alu Alu-Alu介导IFT81 IFT81和MATN3 MATN3中的内部重复性与骨骼发育不良相关联

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摘要

Abstract Skeletal dysplasias are a diverse group of rare Mendelian disorders with clinical and genetic heterogeneity. Here, we used targeted copy number variant (CNV) screening and identified intragenic exonic duplications, formed through Alu‐Alu fusion events, in two individuals with skeletal dysplasia and negative exome sequencing results. First, we detected a homozygous tandem duplication of exon 9 and 10 in IFT81 in a boy with Jeune syndrome, or short‐rib thoracic dysplasia (SRTD) (MIM# 208500). Western blot analysis did not detect any wild‐type IFT81 protein in fibroblasts from the patient with the IFT81 duplication, but only a shorter isoform of IFT81 that was also present in the normal control samples. Complementary zebrafish studies suggested that loss of full‐length IFT81 protein but expression of a shorter form of IFT81 protein affects the phenotype while being compatible with life. Second, a de novo tandem duplication of exons 2 to 5 in MATN3 was identified in a girl with multiple epiphyseal dysplasia (MED) type 5 (MIM# 607078). Our data highlights the importance of detection and careful characterization of intragenic duplication CNVs, presenting them as a novel and very rare genetic mechanism in IFT81 ‐related Jeune syndrome and MATN3 ‐related MED.
机译：摘要骨骼发育不良是一种不同群罕见的孟德尔疾病，具有临床和遗传异质性。在这里，我们使用目标拷贝数变体（CNV）筛选并确定通过Alu-Alu融合事件形成的intraceNic exonic重复，在两个具有骨骼发育不良和负exome测序结果的两种中形成。首先，我们检测到JENE综合征或短肋骨发育不良（SRTD）（MIM＃208500）中的IFT81在IFT81中的纯合串联重复。 Western印迹分析没有使用IFT81重复的来自患者的成纤维细胞中的任何野生型IFT81蛋白，但仅在正常对照样品中存在的IFT81的短同种型。互补的斑马鱼研究表明，损失全长IFT81蛋白，但表达较短的IFT81蛋白的表达影响了表型，同时与寿命兼容。其次，在MATN3中的德诺串联重复外显子2至5，在具有多种骨骺发育不良（MED）5型（MIM＃607078）的女孩中鉴定在一个女孩中。我们的数据突出了检测和仔细表征内瘤复制CNV的重要性，将其作为IFT81-相关的JENEEN综合征和MATN3 -Related Med的新颖且非常罕见的遗传机制。

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  • 来源
    《Human mutation》 |2018年第10期|共12页
  • 作者

    Pettersson Maria; Vaz Raquel; Hammarsj? Anna; Eisfeldt Jesper; Carvalho Claudia M.B.; Hofmeister Wolfgang; Tham Emma; Horemuzova Eva; Voss Ulrika; Nishimura Gen; Klintberg Bo; Nordgren Ann; Nilsson Daniel; Grigelioniene Giedre; Lindstrand Anna;

  • 作者单位

    Department of Molecular Medicine and SurgeryKarolinska University HospitalStockholm Sweden;

    Department of Molecular Medicine and Surgery and Center for Molecular MedicineKarolinska;

    Department of Molecular Medicine and SurgeryKarolinska University HospitalStockholm Sweden;

    Department of Molecular Medicine and Surgery and Center for Molecular MedicineKarolinska;

    Department of Molecular and Human GeneticsBaylor College of MedicineHouston Texas;

    Department of Molecular Medicine and Surgery and Center for Molecular MedicineKarolinska;

    Department of Molecular Medicine and SurgeryKarolinska University HospitalStockholm Sweden;

    Department of Women's and Children's HealthKarolinska University HospitalStockholm Sweden;

    Department of Pediatric RadiologyKarolinska University HospitalStockholm Sweden;

    Intractable Disease CenterSaitama University HospitalSaitama Japan;

    Department of PediatricsVisby HospitalVisby Sweden;

    Department of Molecular Medicine and SurgeryKarolinska University HospitalStockholm Sweden;

    Department of Molecular Medicine and SurgeryKarolinska University HospitalStockholm Sweden;

    Department of Molecular Medicine and SurgeryKarolinska University HospitalStockholm Sweden;

    Department of Molecular Medicine and SurgeryKarolinska University HospitalStockholm Sweden;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 医学遗传学;
  • 关键词

    IFT81; intragenic duplication; Jeune syndrome; MATN3; multiple epiphyseal dysplasia; whole genome sequencing; zebrafish;

    机译：IFT81;腺体复制;JENEEN综合征;MATN3;多种骨骺发育不良;全基因组测序;斑马鱼;

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