Department of Molecular Medicine

Department of Molecular Medicine

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Rare and Undiagnosed genetic Disorders

The Japan Agency for Medical Research and Development launched the Initiative on Rare and Undiagnosed Diseases (IRUD) in 2015. IRUD is trying to construct a comprehensive network between medical centers treating intractable diseases and an international data-sharing framework. Osaka Women’s and Children’s Hospital contributes to IRUD as a major medical center in the Kansai area since 2015. Many patients with various genetic disorders visit our hospital. Our department extensively carry out molecular diagnosis of these patients. Analysis centers apply next-generation sequencing systems for undiagnosed registrants. Half of the patients come to final diagnosis. We have contributed for elucidating some novel pathogenic genes.

Our research institute investigates the molecular and cellular bases of diseases and developing novel approaches to diagnosis and treatment. Our medical center promotes appropriate cooperation between clinical departments and the research institute. Model organisms are important tools in rare disease research. In the future, we will try to create a genetically susceptible model that will act as a useful tool to predict the effects of treatment on these patients.

CDG diagnosis support project

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. We are developing various MS-based methods for glycobiology and proteomics.

Applying the method to molecular diagnosis, we have reported that the Congenital Disorders of Glycosylation (CDG) to account for 1 % of the patients with unknown causes of developmental disorders in Japan.

Cell-to-Cell Fusion

Cellular fusion is an intriguing process in the differentiation of trophoblasts, myoblasts and osteoclasts. We identified an actin-binding protein calponin-3 to be involved in cytoskeletal rearrangement required for cell fusion. The knock-out mice of this molecule show various types of “body wall closure defects”, which are by far the most frequent among congenital anomalies, i.e. neural tube defects (NTDs), heart anomaly, omphalocele, cleft palate and so on, in humans. We focus on NTDs and are going to build an experimental system to look for a method of preventing the defects.



Nobuhiko Okamoto, M.D.

Chief Scientist

Shibukawa Yukinao, M.D.,Ph.D.

Research Fellow

Suganya Thanasegaran, Ph.D.

Technical Assistant Etsuko Daimon
Natsuko Yamazaki



  1. Phenotypic and mutational spectrum of ROR2-related Robinow syndrome. Lima AR, Ferreira BM, Zhang C, Jolly A, Du H, WhiteJJ, Dawood M, Lins TC, Chiabai MA, van Beusekom E, Cordoba MS, Caldas Rosa ECC, Kayserili H, Kimonis V, Wu E, Mellado C, Aggarwal V, Richieri-Costa A, Brunoni D, Canó TM, Jorge AAL, Kim CA, Honjo R, Bertola DR, Dandalo-Girardi RM, Bayram Y, Gezdirici A, Yilmaz-Gulec E, Gumus E, Yilmaz GC, Okamoto N, Ohashi H, Coban-Akdemir Z, Mitani T, Jhangiani SN, Muzny DM, Regattieri NAP, Pogue R, Pereira RW, Otto PA, Gibbs RA, Ali BR, van Bokhoven H, Brunner HG, Reid Sutton V, Lupski JR, Vianna-Morgante AM, Carvalho CMB, Mazzeu JF. Hum Mutat. 2022 Jul;43(7):900-918.

  2. Tachibana N, Hosono K, Nomura S, Arai S, Torii K, Kurata K, Sato M, Shimakawa S, Azuma N, Ogata T, Wada Y, Okamoto N, Saitsu H, Nishina S, Hotta Y.
    Genes (Basel). Maternal Uniparental Isodisomy of Chromosome 4 and 8 in Patients with Retinal Dystrophy: SRD5A3-Congenital Disorders of Glycosylation and RP1-Related Retinitis Pigmentosa.
    Genes (Basel). 2022 Feb 16;13(2):359.

  3. Suzuki H, Nozaki M, Yoshihashi H, Imagawa K, Kajikawa D, Yamada M, Yamaguchi Y, Morisada N, Eguchi M, Ohashi S, Ninomiya S, Seto T, Tokutomi T, Hida M, Toyoshima K, Kondo M, Inui A, Kurosawa K, Kosaki R, Ito Y, Okamoto N, Kosaki K, Takenouchi T. Genome Analysis in Sick Neonates and Infants: High-yield Phenotypes and Contribution of Small Copy Number Variations.
    J Pediatr. 2022 May;244:38-48.e1.

  4. Nagai K, Niihori T, Okamoto N, Kondo A, Suga K, Ohhira T, Hayabuchi Y, Homma Y, Nakagawa R, Ifuku T, Abe T, Mizuguchi T, Matsumoto N, Aoki Y.  Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome.
    Hum Mutat. 2022 Jan;43(1):3-15.

  5. Okamoto N, Miya F, Tsunoda T, Kanemura Y, Saitoh S, Kato M, Yanagi K, Kaname T, Kosaki K. Four pedigrees with aminoacyl-tRNA synthetase abnormalities.
    Neurol Sci. 2022 Apr;43(4):2765-2774.


  1. Okamoto N, Ohto T, Enokizono T, Wada Y, Kohmoto T, Imoto I, Haga Y, Seino J, Suzuki T. Siblings with MAN1B1-CDG Showing Novel Biochemical Profiles. Cells. 2021 Nov 10;10(11):3117.

  2. Daimon E, Shibukawa Y, Thanasegaran S, Yamazaki N, Okamoto N.  Macrothrombocytopenia of Takenouchi-Kosaki syndrome is ameliorated by CDC42 specific- and lipidation inhibitors in MEG-01 cells. Sci Rep. 2021 Sep 9;11(1):17990. 

  3. Hiraide T, Wada Y, Matsubayashi T, Kadoya M, Masunaga Y, Ohkubo Y, Nakashima M, Okamoto N, Ogata T, Saitsu H. 1. Novel ALG12 variants and hydronephrosis in siblings with impaired N-glycosylation.
    Brain Dev. 2021 Oct;43(9):945-951.

  4. Masunaga Y, Mochizuki M, Kadoya M, Wada Y, Okamoto N, Fukami M, Kato F, Saitsu H, Ogata T. Primary ovarian insufficiency in a female with phosphomannomutase-2 gene (PMM2) mutations for congenital disorder of glycosylation.
    Endocr J. 2021 May 28;68(5):605-611.

  5. Yamamoto-Shimojima K, Akagawa H, Yanagi K, Kaname T, Okamoto N, Yamamoto T.
    Deep intronic deletion in intron 3 of PLP1 is associated with a severe phenotype of Pelizaeus-Merzbacher disease.
    Hum Genome Var. 2021 Apr 1;8(1):14.

  6. Okamoto N, Miya F, Kitai Y, Tsunoda T, Kato M, Saitoh S, Kanemura Y, Kosaki K. Homozygous ADCY5 mutation causes early-onset movement disorder with severe intellectual disability.
    Neurol Sci. 2021 Jul;42(7):2975-2978.

  7. Faundes V, Goh S, Akilapa R, Bezuidenhout H, Bjornsson HT, Bradley L, Brady AF, Brischoux-Boucher E, Brunner H, Bulk S, Canham N, Cody D, Dentici ML, Digilio MC, Elmslie F, Fry AE, Gill H, Hurst J, Johnson D, Julia S, Lachlan K, Lebel RR, Byler M, Gershon E, Lemire E, Gnazzo M, Lepri FR, Marchese A, McEntagart M, McGaughran J, Mizuno S, Okamoto N, Rieubland C, Rodgers J, Sasaki E, Scalais E, Scurr I, Suri M, van der Burgt I, Matsumoto N, Miyake N, Benoit V, Lederer D, Banka S. Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2.
    Genet Med. 2021 Jul;23(7):1202-1210.

  8. Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities. Chowdhury F, Wang L, Al-Raqad M, Amor DJ, Baxová A, Bendová Š, Biamino E, Brusco A, Caluseriu O, Cox NJ, Froukh T, Gunay-Aygun M, Hančárová M, Haynes D, Heide S, Hoganson G, Kaname T, Keren B, Kosaki K, Kubota K, Lemons JM, Magriña MA, Mark PR, McDonald MT, Montgomery S, Morley GM, Ohnishi H, Okamoto N, Rodriguez-Buritica D, Rump P, Sedláček Z, Schatz K, Streff H, Uehara T, Walia JS, Wheeler PG, Wiesener A, Zweier C, Kawakami K, Wentzensen IM, Lalani SR, Siu VM, Bi W, Balci TB.
    Genet Med. 2021 Jul;23(7):1234-1245.

  9. Zarate YA, Uehara T, Abe K, Oginuma M, Harako S, Ishitani S, Lehesjoki AE, Bierhals T, Kloth K, Ehmke N, Horn D, Holtgrewe M, Anderson K, Viskochil D, Edgar-Zarate CL, Sacoto MJG, Schnur RE, Morrow MM, Sanchez-Valle A, Pappas J, Rabin R, Muona M, Anttonen AK, Platzer K, Luppe J, Gburek-Augustat J, Kaname T, Okamoto N, Mizuno S, Kaido Y, Ohkuma Y, Hirose Y, Ishitani T, Kosaki K. CDK19-related disorder results from both loss-of-function and gain-of-function de novo missense variants.
    Genet Med. 2021 Jun;23(6):1050-1057.

  10. Wada Y, Okamoto N.
    Apolipoprotein C-III O-glycoform profiling of 500 serum samples by matrix-assisted laser desorption/ionization mass spectrometry for diagnosis of congenital disorders of glycosylation.
    J Mass Spectrom. 2021 Apr;56(4):e4597.

  11. Anzai R, Tsuji M, Yamashita S, Wada Y, Okamoto N, Saitsu H, Matsumoto N, Goto T.
    Congenital disorders of glycosylation type IIb with MOGS mutations cause early infantile epileptic encephalopathy, dysmorphic features, and hepatic dysfunction.
    Brain Dev. 2021 Mar;43(3):402-410.

  12. Tajima D, Nakamura T, Ichinose F, Okamoto N, Tomonoh Y, Uda K, Furukawa R, Tashiro K, Matsuo M. Transient hypoglycorrhachia with paroxysmal abnormal eye movement in early infancy. Brain Dev. 2021 Mar;43(3):482-485.

  13. Sakamoto M, Iwama K, Sekiguchi F, Mashimo H, Kumada S, Ishigaki K, Okamoto N, Behnam M, Ghadami M, Koshimizu E, Miyatake S, Mitsuhashi S, Mizuguchi T, Takata A, Saitsu H, Miyake N, Matsumoto N. Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy.
    J Hum Genet. 2021 Apr;66(4):401-407.

  14. izuguchi T, Okamoto N, Yanagihara K, Miyatake S, Uchiyama Y, Tsuchida N, Hamanaka K, Fujita A, Miyake N, Matsumoto N. Pathogenic 12-kb copy-neutral inversion in syndromic intellectual disability identified by high-fidelity long-read sequencing.
    Genomics. 2021 Jan;113(1 Pt 2):1044-1053.

  15. Uchiyama Y, Yamaguchi D, Iwama K, Miyatake S, Hamanaka K, Tsuchida N, Aoi H, Azuma Y, Itai T, Saida K, Fukuda H, Sekiguchi F, Sakaguchi T, Lei M, Ohori S, Sakamoto M, Kato M, Koike T, Takahashi Y, Tanda K, Hyodo Y, Honjo RS, Bertola DR, Kim CA, Goto M, Okazaki T, Yamada H, Maegaki Y, Osaka H, Ngu LH, Siew CG, Teik KW, Akasaka M, Doi H, Tanaka F, Goto T, Guo L, Ikegawa S, Haginoya K, Haniffa M, Hiraishi N, Hiraki Y, Ikemoto S, Daida A, Hamano SI, Miura M, Ishiyama A, Kawano O, Kondo A, Matsumoto H, Okamoto N, Okanishi T, Oyoshi Y, Takeshita E, Suzuki T, Ogawa Y, Handa H, Miyazono Y, Koshimizu E, Fujita A, Takata A, Miyake N, Mizuguchi T, Matsumoto N.
    Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses. Hum Mutat. 2021 Jan;42(1):50-65.

  16. Malhotra A, Ziegler A, Shu L, Perrier R, Amlie-Wolf L, Wohler E, Lygia de Macena Sobreira N, Colin E, Vanderver A, Sherbini O, Stouffs K, Scalais E, Serretti A, Barth M, Navet B, Rollier P, Xi H, Wang H, Zhang H, Perry DL, Ferrarini A, Colombo R, Pepler A, Schneider A, Tomiwa K, Okamoto N, Matsumoto N, Miyake N, Taft R, Mao X, Bonneau D.  De novo missense variants in LMBRD2 are associated with developmental and motor delays, brain structure abnormalities and dysmorphic features.
    J Med Genet. 2021 Oct;58(10):712-716.


  1. Uehara T, Abe K, Oginuma M, Ishitani S, Yoshihashi H, Okamoto N, Takenouchi T, Kosaki K, Ishitani T. Pathogenesis of CDK8-associated disorder: two patients with novel CDK8 variants and in vitro and in vivo functional analyses of the variants.
    Sci Rep. 2020 Oct 16;10(1):17575.

  2. Yanagishita T, Imaizumi T, Yamamoto-Shimojima K, Yano T, Okamoto N, Nagata S, Yamamoto T. Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano-like pattern.
    Hum Mutat. 2020 Dec;41(12):2119-2127.

  3. Hamada N, Ito H, Shibukawa Y, Morishita R, Iwamoto I, Okamoto N, Nagata KI. Neuropathophysiological significance of the c.1449T>C/p.(Tyr64Cys) mutation in the CDC42 gene responsible for Takenouchi-Kosaki syndrome.
    Biochem Biophys Res Commun. 2020 Sep 3;529(4):1033-1037. 

  4. Cappuccio G, Sayou C, Tanno PL, Tisserant E, Bruel AL, Kennani SE, Sá J, Low KJ, Dias C, Havlovicová M, Hančárová M, Eichler EE, Devillard F, Moutton S, Van-Gils J, Dubourg C, Odent S, Gerard B, Piton A, Yamamoto T, Okamoto N, Firth H, Metcalfe K, Moh A, Chapman KA, Aref-Eshghi E, Kerkhof J, Torella A, Nigro V, Perrin L, Piard J, Le Guyader G, Jouan T, Thauvin-Robinet C, Duffourd Y, George-Abraham JK, Buchanan CA, Williams D, Kini U, Wilson K; Telethon Undiagnosed Diseases Program, Sousa SB, Hennekam RCM, Sadikovic B, Thevenon J, Govin J, Vitobello A, Brunetti-Pierri N. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.
    Genet Med. 2020 Nov;22(11):1838-1850.

  5. Watanabe H, Higashimoto K, Miyake N, Morita S, Horii T, Kimura M, Suzuki T, Maeda T, Hidaka H, Aoki S, Yatsuki H, Okamoto N, Uemura T, Hatada I, Matsumoto N, Soejima H. DNA methylation analysis of multiple imprinted DMRs in Sotos syndrome reveals IGF2-DMR0 as a DNA methylation-dependent, P0 promoter-specific enhancer.
    FASEB J. 2020 Jan;34(1):960-973.

  6. Choufani S, Gibson WT, Turinsky AL, Chung BHY, Wang T, Garg K, Vitriolo A, Cohen ASA, Cyrus S, Goodman S, Chater-Diehl E, Brzezinski J, Brudno M, Ming LH, White SM, Lynch SA, Clericuzio C, Temple IK, Flinter F, McConnell V, Cushing T, Bird LM, Splitt M, Kerr B, Scherer SW, Machado J, Imagawa E, Okamoto N, Matsumoto N, Testa G, Iascone M, Tenconi R, Caluseriu O, Mendoza-Londono R, Chitayat D, Cytrynbaum C, Tatton-Brown K, Weksberg R. DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.
    Am J Hum Genet. 2020 May 7;106(5):596-610.


Nobuhiko Okamoto, MD.
Osaka Women’s and Children’s Hospital
840 Murodo-cho, Izumi, Osaka 594-1101, Japan

E-mail: genetics@
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