Research Overview

The goals of the Mochida Laboratory are: 1] to understand the molecular basis of genetic disorders of human brain development, 2] to understand neuropathogenesis of congenital infections, particularly Zika virus, and 3] to develop novel treatment strategies for genetic and non-genetic developmental brain disorders. The Mochida Laboratory combines human subject research with cellular and animal models in order to achieve these goals.

Laboratory Projects

  1. Molecular basis of genetic microcephaly and disorders of the cerebellum: We collaborate with clinicians worldwide to enroll individuals and their families with rare genetic disorders affecting the growth of the cerebrum (microcephaly) and cerebellum (cerebellar hypoplasia and cerebellar atrophy). High-throughput sequencing and genomic approaches are applied to identify novel genetic mutations associated with these human disorders. We particularly focus on highly consanguineous populations in the Middle East to effectively identify autosomal recessive disease genes and have published four new genes associated with these disorders since 2013.
  2. Cellular and animal models of human cerebral and cerebellar development: Once candidate pathogenic mutations in novel genes are identified, we create cellular and animal models to understand their function during normal development and the effect of the mutations we identified. We utilize various model systems from cultured cells to vertebrates (zebrafish and mice) and take advantage of cutting-edge technologies, including induced pluripotent stem cells (iPSCs) and CRISPR/Cas9-mediated genome editing. Some of the biological pathways we currently focus on include amino acid metabolism, energy metabolism, and intracellular trafficking.
  3. Neuropathogenesis of congenital Zika syndrome: Congenital Zika virus infection causes serious neurodevelopmental consequences, including microcephaly, collectively known as congenital Zika syndrome. How Zika virus leads to severe brain malformations is poorly understood, and there are no effective prevention or treatment strategies. We have developed a new mouse model of congenital Zika virus infection and are studying this model to understand the effect of Zika virus infection in the developing brain. Further, we are using this model as a platform for developing novel prevention and therapeutic strategies for congenital Zika virus infection.

Research Background

Ganeshwaran H. Mochida, M.D., M.M.Sc. is a Principal Investigator in the Division of Genetics and Genomics at Boston Children’s Hospital and Assistant Professor of Pediatrics at Harvard Medical School. He is a native of Tokyo and graduated summa cum laude from Keio University School of Medicine. After his pediatric internship at Keio University Hospital, Dr. Mochida moved to Boston and completed residency training in pediatric neurology at Massachusetts General Hospital. Subsequently, his postdoctoral research training was in the laboratory of Professor Christopher A. Walsh at Beth Israel Deaconess Medical Center. He also completed the Clinical Investigator Training Program at Beth Israel Deaconess Medical Center and Harvard-MIT Division of Health Sciences and Technology, and received a Master of Medical Sciences degree from Harvard Medical School. He established his research laboratory in the Division of Genetics and Genomics at Boston Children’s Hospital in 2013.

Selected Publications

  1. Mochida GH*, Ganesh VS*, de Michelena MI, Dias H, Atabay KD, Kathrein KL, Huang HT, Hill RS, Felie JM, Rakiec D, Gleason D, Hill AD, Malik AN, Barry BJ, Partlow JN, Tan WH, Glader LJ, Barkovich AJ, Dobyns WB, Zon LI, Walsh CA. CHMP1A encodes an essential regulator of BMI1- INK4A in cerebellar development. Nat Genet. 2012;44(11):1260-4. PMCID: PMC3567443. (*equal contribution)
  2. Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A, Al-Turki S, Baple EL, Patton MA, Al-Memar AY, Hurles ME, Partlow JN, Hill RS, Evrony GD, Servattalab S, Markianos K, Walsh CA, Crosby AH*, Mochida GH*. Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology 2015;84:1745-50. PMCID: PMC4424132. (*equal contribution)
  3. Nakayama T, Al-Maawali A, El-Quessny M, Rajab A, Khalil S, Stoler JM, Tan WH, Nasir R, Schmitz-Abe K, Hill RS, Partlow JN, Al-Saffar M, Servattalab S, LaCoursiere CM, Tambunan DE, Coulter ME, Elhosary PC, Gorski G, Barkovich AJ, Markianos K, Poduri A, Mochida GH. Mutations in PYCR2, encoding pyrroline-5-carboxylate reductase 2, cause microcephaly and hypomyelination. Am J Hum Genet 2015;96:709-19. PMCID: PMC4570282.

Education

Residency

Massachusetts General Hospital
Boston MA

Fellowship

Massachusetts General Hospital
Boston MA

Publications

  1. Spotlight on Hemorrhagic Destruction of the Brain, Subependymal Calcification, and Congenital Cataracts (HDBSCC). Eye Brain. 2024; 16:55-63. View Abstract
  2. Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria. JAMA Neurol. 2023 09 01; 80(9):980-988. View Abstract
  3. Integrative systems biology characterizes immune-mediated neurodevelopmental changes in murine Zika virus microcephaly. iScience. 2023 Jul 21; 26(7):106909. View Abstract
  4. Bi-allelic variants in INTS11 are associated with a complex neurological disorder. Am J Hum Genet. 2023 05 04; 110(5):774-789. View Abstract
  5. The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2. Genet Med. 2022 11; 24(11):2240-2248. View Abstract
  6. Biallelic loss-of-function variants in WDR11 are associated with microcephaly and intellectual disability. Eur J Hum Genet. 2021 11; 29(11):1663-1668. View Abstract
  7. Zika Virus: Learning from the Past as We Prepare for the Future. J Pediatr. 2020 07; 222:15-16. View Abstract
  8. Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival. Genet Med. 2020 06; 22(6):1040-1050. View Abstract
  9. Holoprosencephaly in Kabuki syndrome. Am J Med Genet A. 2020 03; 182(3):441-445. View Abstract
  10. Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly. Dev Cell. 2019 12 16; 51(6):713-729.e6. View Abstract
  11. Clinical and neurodevelopmental features in children with cerebral palsy and probable congenital Zika. Brain Dev. 2019 Aug; 41(7):587-594. View Abstract
  12. PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features. Am J Med Genet B Neuropsychiatr Genet. 2018 12; 177(8):736-745. View Abstract
  13. Congenital brain abnormalities during a Zika virus epidemic in Salvador, Brazil, April 2015 to July 2016. Euro Surveill. 2018 11; 23(45). View Abstract
  14. The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles. Cell Rep. 2018 07 24; 24(4):973-986.e8. View Abstract
  15. Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy. Hum Mutat. 2017 10; 38(10):1348-1354. View Abstract
  16. Integrated genome and transcriptome sequencing identifies a noncoding mutation in the genome replication factor DONSON as the cause of microcephaly-micromelia syndrome. Genome Res. 2017 08; 27(8):1323-1335. View Abstract
  17. Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate. Neuron. 2016 Nov 23; 92(4):813-828. View Abstract
  18. Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features. Proc Natl Acad Sci U S A. 2016 09 20; 113(38):E5598-607. View Abstract
  19. Novel loss-of-function variants in DIAPH1 associated with syndromic microcephaly, blindness, and early onset seizures. Am J Med Genet A. 2016 Feb; 170A(2):435-440. View Abstract
  20. Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination. Am J Hum Genet. 2015 May 07; 96(5):709-19. View Abstract
  21. Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology. 2015 Apr 28; 84(17):1745-50. View Abstract
  22. Katanin p80 regulates human cortical development by limiting centriole and cilia number. Neuron. 2014 Dec 17; 84(6):1240-57. View Abstract
  23. Neuropsychological function in a child with 18p deletion syndrome: a case report. Cogn Behav Neurol. 2014 Sep; 27(3):160-5. View Abstract
  24. Case records of the Massachusetts General Hospital. Case 27-2014. A 10-month-old boy with microcephaly and episodic cyanosis. N Engl J Med. 2014 Aug 28; 371(9):847-58. View Abstract
  25. Studying rare genetic disorders in child neurology--the need for an international network of collaboration. Dev Med Child Neurol. 2014 May; 56(5):412. View Abstract
  26. Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am J Hum Genet. 2014 Apr 03; 94(4):547-58. View Abstract
  27. METTL23, a transcriptional partner of GABPA, is essential for human cognition. Hum Mol Genet. 2014 Jul 01; 23(13):3456-66. View Abstract
  28. Posterior fossa in primary microcephaly: relationships between forebrain and mid-hindbrain size in 110 patients. Neuropediatrics. 2014 Apr; 45(2):93-101. View Abstract
  29. Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans. Neurology. 2013 Oct 15; 81(16):1378-86. View Abstract
  30. Delineation of the clinical, molecular and cellular aspects of novel JAM3 mutations underlying the autosomal recessive hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Hum Mutat. 2013 Mar; 34(3):498-505. View Abstract
  31. Using whole-exome sequencing to identify inherited causes of autism. Neuron. 2013 Jan 23; 77(2):259-73. View Abstract
  32. CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. Nat Genet. 2012 Nov; 44(11):1260-4. View Abstract
  33. Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]. Am J Hum Genet. 2011 May 13; 88(5):536-47. View Abstract
  34. A homozygous mutation in the tight-junction protein JAM3 causes hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Am J Hum Genet. 2010 Dec 10; 87(6):882-9. View Abstract
  35. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet. 2010 Nov; 42(11):1015-20. View Abstract
  36. Developmental and degenerative features in a complicated spastic paraplegia. Ann Neurol. 2010 Apr; 67(4):516-25. View Abstract
  37. A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly. Am J Hum Genet. 2009 Dec; 85(6):897-902. View Abstract
  38. Genetics and biology of microcephaly and lissencephaly. Semin Pediatr Neurol. 2009 Sep; 16(3):120-6. View Abstract
  39. [Molecular genetics of lissencephaly and microcephaly]. Brain Nerve. 2008 Apr; 60(4):437-44. View Abstract
  40. A novel form of lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet A. 2007 Dec 01; 143A(23):2761-7. View Abstract
  41. An autosomal recessive form of spastic cerebral palsy (CP) with microcephaly and mental retardation. Am J Med Genet A. 2006 Jul 15; 140(14):1504-10. View Abstract
  42. ASPM mutations identified in patients with primary microcephaly and seizures. J Med Genet. 2005 Sep; 42(9):725-9. View Abstract
  43. The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein. Hum Mol Genet. 2005 Aug 01; 14(15):2155-65. View Abstract
  44. Cortical malformation and pediatric epilepsy: a molecular genetic approach. J Child Neurol. 2005 Apr; 20(4):300-3. View Abstract
  45. Broader geographical spectrum of Cohen syndrome due to COH1 mutations. J Med Genet. 2004 Jun; 41(6):e87. View Abstract
  46. Genetic basis of developmental malformations of the cerebral cortex. Arch Neurol. 2004 May; 61(5):637-40. View Abstract
  47. Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion. PLoS Biol. 2004 May; 2(5):E126. View Abstract
  48. Protein-truncating mutations in ASPM cause variable reduction in brain size. Am J Hum Genet. 2003 Nov; 73(5):1170-7. View Abstract
  49. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology. 2003 May 27; 60(10):1664-7. View Abstract
  50. ASPM is a major determinant of cerebral cortical size. Nat Genet. 2002 Oct; 32(2):316-20. View Abstract
  51. Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum Mol Genet. 2001 Aug 15; 10(17):1775-83. View Abstract
  52. Molecular genetics of human microcephaly. Curr Opin Neurol. 2001 Apr; 14(2):151-6. View Abstract
  53. A two-year-old female with methylmalonic acidemia and progressive low density lesions in the basal ganglia on CT scans. Keio J Med. 1999 Dec; 48(4):204-10. View Abstract
  54. Another case of internal carotid artery dissection after mandibular osteotomy. J Oral Maxillofac Surg. 1998 Jan; 56(1):115-6. View Abstract

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