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Page 14 of 17 Matsushita et al. Hepatoma Res 2018;4:61 I http://dx.doi.org/10.20517/2394-5079.2018.81

syndrome patients were present in 15 of 28 individuals (53.6%), whereas 4 (14.3%) individuals had other
[59]
pathogenic variants such as RERE, KMT2D, EP300, or FIR/PUF60 . A two base pair deletion was identified
in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome
[60]
(Verheij syndrome) that shows intellectual disability . In 2013, patients with microdeletions of chromosome
8q24.3 including FIR/PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and
[61]
cardiac defects were found in six patients with variants in FIR/PUF60 . Eye coloboma and complex cardiac
malformations belong to the clinical spectrum of PUF60 variants [62,63] . The fetus presented atrioventricular
septal defect and hypoplastic aortic arch, facial dysmorphism, microretrognathia, dysmorphic ears,
[64]
clinodactyly of the 5th digit on both hands, mild rocker bottom feet and abnormal third sacral vertebra . An
individual was reported with microcephaly, short stature, intellectual disability, and heart defects with a de
[65]
novo c.505C > T variant leading to a p.His169Tyr change in PUF60 . The publications that show the direct
interaction between FIR/PUF60 deficiency and human disease have been accumulating [Table 1]. FIR/PUF60
deficiency-associated amino-acid substitutions, even within a single RNA recognition motif, altered selection
of competing 3’ splice sites (3’ss) and branch points of a FIR/PUF60-dependent exon and the 3’ss choice was
[65]
also influenced by AS of FIR/PUF60 . FIR/FIRΔexon2/PUF60 is a promising target to the development of
cancer diagnosis and therapies directed HBV, HCV, FBW7 as well as c-Myc. Together, FIR/PUF60/FIRΔexon2
are multifunctional through AS and applicable for clinical use for HBV suppression especially for hepatoma
treatment.

DECLARATIONS
Acknowledgements
The authors appreciate Dr Hiroyuki Osada and his coworkers (RIKEN, Wako, Saitama, Japan) for screening
compounds bound to FIR/FIRΔexon2 from a chemical library which was a collection of the isolates from
natural products.

Authors’ contributions
Made substantial contributions to conception and design of the study and performed data analysis and
interpretation: Matsushita K
Performed data acquisition, as well as provided administrative, technical, and material support: Hoshino T

Availability of data and materials
Materials used in this study are generally available for readers as described in th materials and methods.

Financial support and sponsorship
This study was supported in part by Grant-in-Aid 26460667 for priority areas in cancer research from “the
Ministry of Education, Science, Sports and Culture of Japan” (KAKENHI), AMED (Japan Agency for
Medical Research and Development), “Chiba Foundation for Health Promotion & Disease Prevention” and
was partly supported by Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa
University to K.M.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.