Isolation of a causative gene for microphthalmia with limb anomaly

• Project/Area Number: 22790333
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Human genetics
• Research Institution: Yokohama City University
• Principal Investigator: MASUKO Kiyomi 横浜市立大学, 医学研究科, 技術吏員 (00535817)
• Research Collaborator: MATSUMOTO Naomichi 横浜市立大学, 医学研究科, 教授 (80325638) ; SAITSU Hirotomo 横浜市立大学, 医学部, 准教授 (40402838)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 分子遺伝学 / 眼球低形成 / 四肢異常 / 常染色体劣性遺伝 / マウス

Research Abstract

Microphthalmia with limb anomalies(MLA) is a rare autosomal recessive disorder, presenting with anophthalmia/microphthalmia and hand/foot malformation. We mapped the MLA locus to 14_q24 and successfully identified three homozygous(a nonsense and two splice site) mutations in the SPARC(secreted protein acidic and rich in cysteine) related modular calcium binding 1(SMOC1) gene 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/hypoplasia of optic nerves, hypoplastic fibula/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 protein is essential for ocular and limb development in both humans and mice.

Research Products

• [Journal Article] SMOC1 is essential for ocular and limb development in humans and mice (2011)
  • Author(s): kada I, Hamanoue H, Terada K, Tohma T, Megarbane A, Chouery E, Abou-Ghoch J, Jalkh N, Cogulu O, Ozkinay F, Horie K, Takeda J, Furuichi T, Ikegawa S, Nishiyama K, Miyatake S, Nishimura A, Mizuguchi T, Niikawa N, Hirahara F, Kaname T, Yoshiura K-i, Tsurusaki Y, Doi H, Miyake N, Furukawa T, Matsumoto N, Saitsu H
  • Journal Title: Am J Hum Genet Volume: 88(1) Pages: 30-41
• [Journal Article] Paternal mosaicism of a STXBP1 mutation in Ohtahara syndrome (2011)
  • Author(s): Saitsu H, Hoshino H, Kato M, Nishiyama K, Okada I, Yoneda Y, Tsurusaki Y, Doi H, Miyake N, Kubota M, Hayasaka K, Matsumoto N.
  • Journal Title: Clin Genet Volume: 80(5) Pages: 484-488
• [Journal Article] Early infantile epileptic encephalopathy associated with the disrupted gene encoding Slit-Robo Rho GTPase activating protein 2(SRGAP2) (2011)
  • Author(s): Saitsu H, Osaka H, Sugiyama S, Kurosawa K, Mizuguchi T, Nishiyama K, Nishimura A, Tsurusaki Y, Doi H, Miyake N, Harada N, Kato M, Matsumoto N.
  • Journal Title: Am J Med Genet Part A Volume: 158(1) Pages: 199-205
• [Journal Article] Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal recessive hypomyelinating leukoencephalopathy (2011)
  • Author(s): Saitsu H, Osaka H, Sasaki M, Takanashi J, Hamada K, Yamashita A, Shiina M, Kondo Y, Nishiyama K, Tsurusaki Y, Miyake N, Doi H, Ogata K, Inoue K, Matsumoto N.
  • Journal Title: Am J Hum Genet Volume: 90(1) Pages: 86-90
• [Journal Article] SMOC1 is essential for ocular and limb development in humans and mice (2011)
  • Author(s): Okada I, et al., Nishiyama K, et al
  • Journal Title: Am J Hum Genet Volume: 88 Pages: 30-41
  • Peer Reviewed
• [Journal Article] Paternal mosaicism of aSTXBP1 mutation in Ohtahara syndrome (2011)
  • Author(s): Saitsu H, et al., Nishiyama K, et al
  • Journal Title: Clin Genet Volume: 80 Pages: 484-488
  • Peer Reviewed
• [Journal Article] Early infantile epileptic encephalopathy associated with the disrupted gene encoding Slit-Robo Rho GTPase activating protein 2 (SRGAP2) (2011)
  • Author(s): Saitsu H, et al., Nishiyama K, et al
  • Journal Title: Am J Med Genet Part A Volume: 158 Pages: 199-205
  • Peer Reviewed
• [Journal Article] Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal recessive hypomyelinating leukoencephalopathy (2011)
  • Author(s): Saitsu H, et al., Nishiyama K
  • Journal Title: Am J Hum Genet Volume: 90 Pages: 86-90
  • Peer Reviewed
• [Journal Article] Dominant negative mutations in α-II spectrin cause early onset West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay (2010)
  • Author(s): Saitsu H, Tohyama J, Kumada T, Egawa K, Hamada K, Okada I, Mizuguchi T, Osaka H, Miyata R, Furukawa T, Haginoya K, Hoshino H, Goto T, Hachiya Y, Yamagata T, Saitoh S, Nagai T, Nishiyama K, Nishimura A, Miyake N, Komada M, Hayashi K, Hirai S, Ogata K, Kato M, Fukuda A, Matsumoto N.
  • Journal Title: Am J Hum Genet Volume: 86(6) Pages: 881-889
• [Journal Article] STXBP1 mutations in severe infantile epilepsies with suppression-burst pattern (2010)
  • Author(s): Saitsu H, Kato M, Okada I, Orii KE, Kondo N, Wada T, Hoshino H, Kubota M, Arai H, Tagawa T, Kimura S, Sudo A, Miyama S, Takami Y, Watanabe T, Nishimura A, Nishiyama K, Miyake N, Osaka H, Hayasaka K, Matsumoto N.
  • Journal Title: Epilepsia Volume: 51(12) Pages: 2397-2405
• [Journal Article] Dominant negative mutations in α-II spectrin cause early onset West syndrome with severe cerebral hypomyelination, spastic quadriplegia, and developmental delay. (2010)
  • Author(s): Saitsu H, others, Nishiyama K, others.
  • Journal Title: Am J Hum Genet Volume: 86 Pages: 881-889
  • Peer Reviewed
• [Journal Article] STXBP1 mutations in severe infantile epilepsies with suppression-burst pattern. (2010)
  • Author(s): Saitsu H, others, Nishiyama K, others.
  • Journal Title: Epilepsia Volume: 51 Pages: 2397-2405
  • Peer Reviewed