Alu-Alu mediated intragenic duplications in IFT81 and MATN3 are associated with skeletal dysplasias.

Autor: Pettersson M; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden., Vaz R; Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden., Hammarsjö A; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden., Eisfeldt J; Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.; Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden., Carvalho CMB; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas., Hofmeister W; Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden., Tham E; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden., Horemuzova E; Department of Women's and Children's Health, Karolinska Institutet and Paediatric Endocrinology Unit, Karolinska University Hospital, Stockholm, Sweden., Voss U; Department of Pediatric Radiology, Karolinska University Hospital, Stockholm, Sweden., Nishimura G; Intractable Disease Center, Saitama University Hospital, Saitama, Japan., Klintberg B; Department of Pediatrics, Visby Hospital, Visby, Sweden., Nordgren A; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden., Nilsson D; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.; Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden., Grigelioniene G; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden., Lindstrand A; Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2018 Oct; Vol. 39 (10), pp. 1456-1467. Date of Electronic Publication: 2018 Aug 22.
DOI: 10.1002/humu.23605
Abstrakt: 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.
(© 2018 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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