title: Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function.
abstract: Loss-of-function mutations in filamin A (FLNA) cause an X-linked dominant disorder with multiple organ involvement. Affected females present with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and Ehlers-Danlos syndrome. These mutations are typically lethal to males, and rare male survivors suffer from failure to thrive, PVNH, and severe cardiovascular and gastrointestinal complications. Here we report two surviving male siblings with a loss-of-function mutation in FLNA. They presented with multiple complications, including valvulopathy, intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). However, these siblings had atypical clinical courses, such as a lack of PVNH and a spontaneous improvement of CIPO. Trio-based whole-exome sequencing revealed a 4-bp deletion in exon 40 that was predicted to cause a lethal premature protein truncation. However, molecular investigations revealed that the mutation induced in-frame skipping of the mutated exon, which led to the translation of a mutant FLNA missing an internal region of 41 amino acids. Functional analyses of the mutant protein suggested that its binding affinity to integrin, as well as its capacity to induce focal adhesions, were comparable to those of the wild-type protein. These results suggested that exon skipping of FLNA partially restored its protein function, which could contribute to amelioration of the siblings' clinical courses. This study expands the diversity of the phenotypes associated with loss-of-function mutations in FLNA.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences (RIKEN-IMS), Yokohama, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Oda
authors.affiliation: Division of Biochemistry, School of Pharmaceutical Science, Kitasato University, Tokyo, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kunishima
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Izawa
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Eitaro
authors.initials: E
authors.lastname: Hiejima
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yasumi
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiraku
authors.initials: H
authors.lastname: Doi
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Katamura
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Department of Genetic Counseling, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan.
authors.forename: Hironao
authors.initials: H
authors.lastname: Numabe
authors.affiliation: Department of Surgery (Hepato-Biliary-Pancreatic and Transplantation), Graduate School of Medicine, Kyoto University, Kyoto, Japan.|Division of Pediatric Surgery, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakase
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences (RIKEN-IMS), Yokohama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hijikata
authors.affiliation: Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences (RIKEN-IMS), Yokohama, Japan.|Department of Human Genome Research, Kazusa DNA Research Institute, Chiba, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.affiliation: Department of Morphological and Biomolecular Research, Nippon Medical School, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Morisaki
authors.affiliation: Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morisaki
authors.affiliation: Division of Pediatrics, Department of Reproductive and Developmental Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nunoi
authors.affiliation: Division of Biochemistry, School of Pharmaceutical Science, Kitasato University, Tokyo, Japan.
authors.forename: Seisuke
authors.initials: S
authors.lastname: Hattori
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Nishikomori
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Heike
mesh_terms: D000328:Adult; D001773:Blood Cells / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics*; D005260:Female; D064448:Filamins / Q000235:genetics* / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D064448:Filamins