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Spontaneous Tyrosinase Mutations Identified in Albinos of Three Wild Frog Species

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Spontaneous Tyrosinase Mutations Identified in Albinos of Three Wild Frog Species Genes Genet. Syst. (2017) 92, p. 189–196 Albino tyrosinase mutations in frogs 189 Spontaneous tyrosinase mutations identified in albinos of three wild frog species Ikuo Miura1*, Masataka Tagami2, Takeshi Fujitani3 and Mitsuaki Ogata4 1Amphibian Research Center, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan 2Gifu World Freshwater Aquarium, 1453 Kawashima-Kasadamachi, Kakamigahara, Gifu 501-6021, Japan 3Higashiyama Zoo and Botanical Gardens Information, 3-70 Higashiyama-Motomachi, Chikusa-ku, Nagoya, Aichi 464-0804, Japan 4Preservation and Research Center, The City of Yokohama, 155-1 Kawaijuku-cho Asahi-ku, Yokohama, Kanagawa 241-0804, Japan (Received 1 November 2016, accepted 9 March 2017; J-STAGE Advance published date: 30 June 2017) The present study reports spontaneous tyrosinase gene mutations identi- fied in oculocutaneous albinos of three Japanese wild frog species, Pelophylax nigromaculatus, Glandirana rugosa and Fejervarya kawamurai. This repre- sents the first molecular analyses of albinic phenotypes in frogs. Albinos of P. nigromaculatus collected from two different populations were found to suffer from frameshift mutations. These mutations were caused by the insertion of a thymine residue within each of exons 1 and 4, while albinos in a third popula- tion lacked three nucleotides encoding lysine in exon 1. Albinos from the former two P. nigromaculatus populations were also associated with splicing variants of mRNA that lacked either exons 2–4 or exon 4. In the other two frog species exam- ined, missense mutations that resulted in amino acid substitutions from glycine to arginine and glycine to aspartic acid were identified in exons 1 and 3, respec- tively. The two glycines in F. kawamurai and G. rugosa, and the lysine deleted in one P. nigromaculatus albino, were highly conserved in vertebrates, which suggested that they were situated in regions of critical importance to tyrosinase function. In fact, the glycine of G. rugosa is located within a predicted copper- binding domain. The five mutations identified in the present study are candidates for causing the albinic phenotypes, and, if directly confirmed, they are all unique among vertebrates, which suggests that molecular analysis of albino frogs could contribute to research on albinos in humans and vertebrates by providing new information about tyrosinase structure and transcript processing. Key words: albino, tyrosinase, mutation, frog, mRNA isoform gene. In humans, tyrosinase has been extensively stud- INTRODUCTION ied due to its applications in both medical and cosmetic The external coloration of organisms plays important sciences. The amino acid and nucleotide sequences of roles in biological functions such as adaptation to the the tyrosinase gene in vertebrates were first determined environment, reproduction and speciation. Coloration is in mice (Yamamoto et al., 1987; Müller et al., 1988) and expressed as a result of color pigments and their cumula- humans (Kwan et al., 1987). Since then, the tyrosinase tive effects in cells in skin, feathers and hair. The bio- gene in humans has been associated with 265 cases of synthesis of melanin, a major color pigment deposited in oculocutaneous albinism type 1 (OCA1), all of which have melanocytes that is mainly black or brown, relies heav- been analyzed and their causative mutations identified ily on tyrosinase, an enzyme that catalyzes two steps (http://www.ifpcs.org/albinism/). in the pathway that produces melanin. Amelanotic In amphibians, external coloration is directly expressed phenotypes are caused by mutations in the tyrosinase by pigment cells in the skin. This is thus highly advan- tageous for researching coloration and has led to exten- sive examination of amphibian coloration in the twentieth Edited by Kiichi Fukui * Corresponding author. E-mail: [email protected] century (Bagnara et al., 1968). Since some Japanese frog DOI: http://doi.org/10.1266/ggs.16-00061 species breed in paddy fields and ponds that are located in 190 I. MIURA et al. close proximity to humans, unusual coloration of tadpoles, ative tyrosinase mutations species- or amphibian-specific, including albinic phenotypes, can easily be detected and or do they also occur in humans? Second, does albinism is frequently reported. Indeed, many cases of color vari- in frogs of the same species taken from different locali- ation in Japanese tadpoles are reported each year (Miura, ties share the same origin, or did albinism arise inde- 2009; Teraoka and Yamaguchi, 2009; Teraoka, 2013). In pendently in different populations? To investigate these previous studies involving the Japanese frog Pelophylax questions, the sequences of tyrosinase genes from albi- nigromaculatus, 13 different kinds of albinos were col- nos showing a completely amelanotic phenotype in three lected from wild populations, stored, and classified based different frog species were determined, with individuals on five distinct loci, one of which was postulated to encode of one species having been collected from three different tyrosinase and produce the completely amelanotic pheno- localities. The mutations identified in the present study type, with pinkish eyes and yellow skin where no mela- were all unique among vertebrates. notic cells, and no deformities in the other two pigment cells of xanthophore and iridophore, are visible (Nishioka MATERIALS AND METHODS and Ueda, 1985; Nishioka et al., 1987). Sequences of tyrosinase cDNA and its associated genomic region were Albino frogs and pigment cell observation All the determined in the wild-type frog of the species (Takase albinos examined in the present study were collected from et al., 1992; Miura et al., 1995). Despite these fortuitous the wild when they were tadpoles, and were then reared conditions, molecular analysis of albino frogs has not pre- at facilities of Hiroshima University or Gifu World Fresh- viously been undertaken. water Aquarium (Fig. 1). Albinic tadpoles of Pelophylax In the present study, two questions regarding albinism nigromaculatus, AK, AI and AH, were collected from in frogs are examined. First, are the associated caus- Kumamoto city, Kumamoto prefecture in 2013 (by Kikuo Fig. 1. External morphology and pigment cells of albino frog specimens. Albinos of Pelophylax nigromaculatus (A, B, C) from Kure city, Hiro-machi (AH), Kumamoto (AK) and Ichinomiya (AI) cities; wild-type frog of P. nigromaculatus (D); and albinos of Glandirana rugosa (E) and Fejervarya kawamurai (F). Pigment cells in the skin of wild-type and albino frogs of AK and AI (P. nigromaculatus) (D’, B’ and C’). Bar indicates 1 cm in A–F and 50 μm in D’, B’ and C’. Albino tyrosinase mutations in frogs 191 Matsumi), Ichinomiya city, Aichi prefecture in 2015 and skin that was taken from the dorsal surface of a frog after Kure city (Hiro-machi), Hiroshima prefecture in 1979, low-temperature anesthesia in iced water was put on a respectively. Albinic tadpoles of Glandirana rugosa and glass slide in Amphibian Ringer solution with a cover- Fejervarya kawamurai were collected from Miyoshi city, slip, and observed under a microscope (Nikon Eclipse 80i/ Hiroshima prefecture in 2000 (by Yoshiharu Takeyasu) Plan Fluor, DS-US/DS-Ri1 camera). Animal care and and Yukuhashi city, Fukuoka prefecture in 2002 (by Manji experimental procedures were conducted under approval Yamamoto), respectively. We used a heterozygous frog of of the Committee for Ethics in Animal Experimentation F. kawamurai, which was an offspring from a cross of the at Hiroshima University (Permit Number: G13-3). albino with a wild-type frog, for molecular analysis in this study. For observation of pigment cells, a small piece of Genomic Southern blot hybridization This hybrid- Fig. 2. Genomic Southern blot hybridization of the tyrosinase gene in Pelophylax nigromaculatus. The exon structure of tyrosinase cDNA is shown at the top. DNA fragments (3.5 kb and a–e) used to con- struct probes are shown in the middle (numbers in parentheses indicate exons). Results of hybridization are shown at the bottom. aa, amino acid sequence; nt, nucleotide sequence. Three PstI sites located within the untranslated region (part of exon 5) divide exon 5 into four parts (5a–d). Restriction sites (P, PstI; D, DdeI; B, BglII; N, NcoI) are indicated by open triangles. Closed triangles indicate 5’ and 3’ ends of cDNA as well as the ends of the five exons. Two predicted copper-binding domains (aa 184–214 and 367–394) are indicated by hatched rectangles, and a transmembrane domain (aa 479–499) by the gray rectangle, under the exon structure. The locations of primers used for amplifying tyrosinase cDNA fragments are shown by arrows; those used for F. kawamurai are located within exons 1 and 5 (see text for the precise nucleotide numbers). Asterisk indicates the stop codon. Size markers are shown to the right of lane (e). 192 I. MIURA et al. ization was performed according to the method of Miura er’s instruction. The primers used for amplification of et al. (1998). DNA (15 μg) cut with PstI was electro- tyrosinase cDNA were as follows: cDNA forward 5’-GAG phoresed in a 0.8% agarose gel and then transferred to GTC TGA GGA GGA TCA CTA GG-3’ and reverse 5’-GGA a nylon membrane in 10 × SSC (1.5 M NaCl and 0.17 M TCG TAG AGT AAT TTC CCA GAG-3’ for P. nigromacu- sodium citrate) after denaturation with 0.5 M NaOH and latus and G. rugosa; and forward 5’-CTC YTR AGC AAG 1.5 M NaCl followed by neutralization with 0.5 M Tris GAR TGT TGC CC-3’ and reverse 5’-TGR TAR TCT TCR and 1.5 M NaCl (pH 7.5), and hybridized with digoxi- GCY TCC ATG AG-3’ for F. kawamurai. The primers genin-labeled probe in 0.05 M sodium phosphate buffer used for amplification of tyrosinase genomic regions were containing 5 × SSC, 10% SDS, 2% blocking solution, 0.1% as follows: exon1 forward 5’-AGT GCA GGT TTG GCT N-lauroylsarcosine and denatured salmon sperm DNA ACA CA-3’and reverse 5’-TGG GCC CCA GAT AGC AGT (60 μg/ml) at 68 °C for 16 h.
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