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SMOC1 is essential for ocular and limb development in humans and mice

Authors:	Okada Ippei Hamanoue Haruka Terada Koji Tohma Takaya Megarbane Andre Chouery Eliane Abou-Ghoch Joelle Jalkh Nadine Cogulu Ozgur Ozkinay Ferda Horie Kyoji Takeda Junji Furuichi Tatsuya Ikegawa Shiro Nishiyama Kiyomi Miyatake Satoko Nishimura Akira Mizuguchi Takeshi Niikawa Norio Hirahara Fumiki Kaname Tadashi Yoshiura Koh-Ichiro Tsurusaki Yoshinori Doi Hiroshi Miyake Noriko Furukawa Takahisa Matsumoto Naomichi Saitsu Hirotomo

Affiliation:	¹Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan;²Department of Obstetrics and Gynecology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan;³Department of Developmental Biology, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, Osaka 565-0874, Japan;⁴Division of Pediatrics, Okinawa Prefectural Nanbu Medical Center & Children's Medical Center, 118-1 Ikyoku, Arakawa, Haebaru, Okinawa 901-1193, Japan;⁵Medical Genetics Unit, St. Joseph University, Beirut 1104-2020, Lebanon;⁶Department of Pediatrics, Ege University Faculty of Medicine, 35100 Bornova-Izmir, Turkey;⁷Department of Social and Environmental Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;⁸Center for Advanced Science and Innovation, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan;⁹Laboratory for Bone and Joint Disease, Center for Genomic Medicine, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;¹⁰Laboratory Animal Facility, Research Center for Medical Sciences, Jikei University School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan;¹¹Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan;¹²Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-12-4, Nagasaki 852-8523, Japan;¹³Department of Medical Genetics, University of the Ryukyus Faculty of Medicine, 207 Uehara, Nishihara, Okinawa 903-0215, Japan

Abstract:	Microphthalmia with limb anomalies (MLA) is a rare autosomal-recessive disorder, presenting with anophthalmia or microphthalmia and hand and/or foot malformation. We mapped the MLA locus to 14q24 and successfully identified three homozygous (one nonsense and two splice site) mutations in the SPARC (secreted protein acidic and rich in cysteine)-related modular calcium binding 1 (SMOC1) in three families. Smoc1 is expressed in the developing optic stalk, ventral optic cup, and limbs of mouse embryos. Smoc1 null mice recapitulated MLA phenotypes, including aplasia or hypoplasia of optic nerves, hypoplastic fibula and bowed tibia, and syndactyly in limbs. A thinned and irregular ganglion cell layer and atrophy of the anteroventral part of the retina were also observed. Soft tissue syndactyly, resulting from inhibited apoptosis, was related to disturbed expression of genes involved in BMP signaling in the interdigital mesenchyme. Our findings indicate that SMOC1/Smoc1 is essential for ocular and limb development in both humans and mice.

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