Journal of Genetics

, 99:7 | Cite as

A novel de novo mutation in the PURA gene associated with a new clinical finding: large brainstem

  • María Elena Rodríguez-García
  • Francisco Javier Cotrina-Vinagre
  • Elena Arranz-Canales
  • Ana Martínez de Aragón
  • Laura Hernández-Sánchez
  • Fátima Rodríguez-Fornés
  • Patricia Carnicero-Rodríguez
  • Montserrat Morales-Conejo
  • Elena Martín-Hernández
  • Francisco Martínez-AzorínEmail author
Research Article


We report the case of a Caucasian Spanish boy, who showed profound neonatal hypotonia, feeding difficulties, apnea, severe developmental delay, epilepsy, bilateral convergent strabismus, poor verbal language development and a large brainstem. Whole-exome sequence uncovered a novel de novo mutation in the purine-rich element binding protein A gene (PURA; NM_005859.4:c.72del:p.(Gly25AlafsTer53)) that encodes the transcriptional activator protein Pur-alpha (PURA). Mutations in this gene have been identified in patients with PURA syndrome, a rare disorder characterized by an early hypotonia, developmental delay, severe intellectual disability with or without epilepsy, and disability in expressive language development. Although, up to 75 cases have been identified worldwide, to the best of our knowledge, this is the first patient described with a brainstem larger than normal. In conclusion, our data expand both genetic and phenotypic spectrum associated with PURA gene mutations.


PURA gene whole-exome sequence brainstem hypotonia developmental delay epilepsy. 



The authors thank the patient and his family for their contribution. This work was supported by the Spanish Instituto de Salud Carlos III (ISCIII) and the European Regional Development Fund (ERDF) (grant PI17/00487 to F.M.-A.). F.J.C.-V. was supported by fellowship from the Instituto de Investigación Hospital 12 de Octubre (i+12). M.E.R-G. was supported by a fellowship from ISCIII and ERDF (grant PI17/00487).


  1. Elhussein N., Alkhathami A. H. A. and Ayad C. E. 2017 Norms for brain stem: a morphometric MRI based study. IOSR-J. Dental Med. Sci. 16, 74–79.Google Scholar
  2. Garbade S. F., Boy N., Heringer J., Kolker S. and Harting I. 2018 Age-related changes and reference values of bicaudate ratio and sagittal brainstem diameters on MRI. Neuropediatrics 49, 269–275.CrossRefGoogle Scholar
  3. Hokkanen S., Feldmann H. M., Ding H., Jung C. K., Bojarski L., Renner-Muller I. et al. 2012 Lack of Pur-alpha alters postnatal brain development and causes megalencephaly. Hum. Mol. Genet. 21, 473–484.CrossRefGoogle Scholar
  4. Hunt D., Leventer R. J., Simons C., Taft R., Swoboda K. J., Gawne-Cain M. et al. 2014 Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability. J. Med. Genet. 51, 806–813.CrossRefGoogle Scholar
  5. Khalili K., Del Valle L., Muralidharan V., Gault W. J., Darbinian N., Otte J. et al. 2003 Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse. Mol. Cell Biol. 23, 6857–6875.CrossRefGoogle Scholar
  6. Lalani S. R., Zhang J., Schaaf C. P., Brown C. W., Magoulas P., Tsai A. C. et al. 2014 Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. Am. J. Hum. Genet. 95, 579–583.CrossRefGoogle Scholar
  7. Lee B. H., Reijnders M. R. F., Abubakare O., Tuttle E., Lape B., Minks K. Q. et al. 2018 Expanding the neurodevelopmental phenotype of PURA syndrome. Am. J. Med. Genet. A 176, 56–67.CrossRefGoogle Scholar
  8. Mayorga L., Gamboni B., Mampel A. and Roque M. 2018 A frame-shift deletion in the PURA gene associates with a new clinical finding: hypoglycorrhachia. Is GLUT1 a new PURA target? Mol. Genet. Metab. 123, 331–336.CrossRefGoogle Scholar
  9. Okamoto N., Nakao H., Niihori T. and Aoki Y. 2017 Patient with a novel purine-rich element binding protein A mutation. Congenit. Anom. (Kyoto) 57, 201–204.CrossRefGoogle Scholar
  10. Qiao Y., Bagheri H., Tang F., Badduke C., Martell S., Lewis S. M. E. et al. 2019 Exome sequencing identified a de novo mutation of PURA gene in a patient with familial Xp22.31 microduplication. Eur. J. Med. Genet. 62, 103–108.CrossRefGoogle Scholar
  11. Raininko R., Autti T., Vanhanen S. L., Ylikoski A., Erkinjuntti T. and Santavuori P. 1994 The normal brain stem from infancy to old age. A morphometric MRI study. Neuroradiology 36, 364–368.CrossRefGoogle Scholar
  12. Reijnders M. R. F., Janowski R., Alvi M., Self J. E., van Essen T. J., Vreeburg M. et al. 2018 PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature. J. Med. Genet. 55, 104–113.CrossRefGoogle Scholar
  13. Rezkalla J., Von Wald T. and Hansen K. A. 2017 Premature thelarche and the PURA syndrome. Obstet. Gynecol. 129, 1037–1039.CrossRefGoogle Scholar
  14. Tanaka A. J., Bai R., Cho M. T., Anyane-Yeboa K., Ahimaz P., Wilson A. L. et al. 2015 De novo mutations in PURA are associated with hypotonia and developmental delay. Cold Spring Harb. Mol. Case Stud. 1, a000356.CrossRefGoogle Scholar
  15. Yoshida T., Yasuda R., Mizuta I., Nakagawa M., Mizuno T. and Group J. A. D. S. 2017 Quantitative evaluation of brain stem atrophy using magnetic resonance imaging in adult patients with alexander disease. Eur. Neurol. 77, 296–302.CrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2020

Authors and Affiliations

  1. 1.Laboratorio de Enfermedades MitocondrialesInstituto de Investigación Hospital 12 de Octubre (i+12)MadridSpain
  2. 2.Departamento de Medicina InternaHospital 12 de OctubreMadridSpain
  3. 3.Servicio de Radiología, Sección de NeurorradiologíaHospital 12 de OctubreMadridSpain
  4. 4.Unidad Pediátrica de Enfermedades Raras, Enfermedades Mitocondriales y Metabólicas HereditariasHospital 12 de OctubreMadridSpain
  5. 5.Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), U723MadridSpain

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