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.
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Acknowledgements
We thank the patients and their family members for participating in our study, Ms Yuki Takaoka for her technical assistance and Dr Hisanori Horiuchi for his kind advice on platelet analysis. This work was supported by grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, and the Japanese Ministry of Health, Labor, and Welfare.
Author Contributions
HO performed genetic and molecular analyses, and wrote the paper. TS, KN, KI, EH, H Nunoi and SH performed molecular investigations of the FLNA mutation. HS and SK performed imaging analysis of blood cells. H Numabe performed genetic counseling and performed genetic analyses. AH and OO performed whole-exome sequencing. HM and TM performed genetic analysis of Marfan syndrome-related genes and whole-exome sequencing. HD, KK, SO and H Nakase participated in the patients’ diagnosis and contributed to writing the manuscript. TK, TY, RN and TH designed the study and contributed to writing the manuscript.
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Oda, H., Sato, T., Kunishima, S. et al. Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function. Eur J Hum Genet 24, 408–414 (2016). https://doi.org/10.1038/ejhg.2015.119
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DOI: https://doi.org/10.1038/ejhg.2015.119
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