PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment

Brain. 2017 Apr 1;140(4):940-952. doi: 10.1093/brain/awx014.

Massimo Zollo ¹ ² ³, Mustafa Ahmed ⁴, Veronica Ferrucci ¹ ² ³, Vincenzo Salpietro ⁵, Fatemeh Asadzadeh ¹ ², Marianeve Carotenuto ¹ ², Reza Maroofian ⁴, Ahmed Al-Amri ⁶ ⁷, Royana Singh ⁸, Iolanda Scognamiglio ¹ ², Majid Mojarrad ⁹ ¹⁰, Luca Musella ¹ ², Angela Duilio ¹¹, Angela Di Somma ¹¹, Ender Karaca ¹², Anna Rajab ⁷, Aisha Al-Khayat ¹³, Tribhuvan Mohan Mohapatra ⁸, Atieh Eslahi ⁹, Farah Ashrafzadeh ⁹ ¹⁴, Lettie E Rawlins ⁴, Rajniti Prasad ¹⁵, Rashmi Gupta ⁸, Preeti Kumari ⁸, Mona Srivastava ⁸ ¹⁶, Flora Cozzolino ², Sunil Kumar Rai ⁸, Maria Monti ² ¹¹, Gaurav V Harlalka ⁴, Michael A Simpson ¹⁷, Philip Rich ¹⁸, Fatema Al-Salmi ¹³, Michael A Patton ⁴ ¹³ ¹⁹, Barry A Chioza ⁴, Stephanie Efthymiou ⁵, Francesca Granata ²⁰, Gabriella Di Rosa ²¹, Sarah Wiethoff ⁵, Eugenia Borgione ²², Carmela Scuderi ²², Kshitij Mankad ²³, Michael G Hanna ⁵ ²⁴, Piero Pucci ² ¹¹, Henry Houlden ⁵, James R Lupski ¹² ²⁵ ²⁶ ²⁷, Andrew H Crosby ⁴, Emma L Baple ⁴

Affiliations

1 Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.
2 CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
3 European School of Molecular Medicine, SEMM, University of Milan, Italy.
4 Medical Research (Level 4), RILD Wellcome Wolfson Centre, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK.
5 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
6 Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, UK.
7 National Genetic Centre, Directorate General of Royal Hospital, Ministry of Health, Muscat, Sultanate of Oman.
8 Molecular Genetics, Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.
9 Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
10 Medical Genetics Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
11 Dipartimento di Scienze Chimiche, Università Federico II, Naples, Italy.
12 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
13 Department of Biology, Sultan Qaboos University, PO Box 36, Post code 123, Sultanate of Oman.
14 Department of Pediatric Neurology, Ghaem Medical Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Zip Code- 9919991766, Iran.
15 Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.
16 Department of Psychiatry, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.
17 Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
18 Department of Neuroradiology, St. George's Hospital, London, UK.
19 Genetics Research Centre, St. George's, University of London, London, SW17 0RE, UK.
20 Unit of Neuroradiology, Department of Biomedical Science and Morphological and Functional Images, University of Messina, Messina, Italy.
21 Unit of Child Neurology and Psychiatry, Department of Human Pathology of the Adult and Developmental Age, University of Messina, Messina, Italy.
22 Unit of Neuromuscular disorders, IRCCS Oasi Maria SS Troina, Enna, Italy.
23 Department of Neuroradiology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
24 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK.
25 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
26 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
27 Texas Children's Hospital, Houston, TX 77030, USA.

PMID: 28334956 DOI: 10.1093/brain/awx014

Abstract

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in Cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.

Keywords

PRUNE1; developmental delay; microcephaly; microtubule polymerization, tubulinopathy; normal brain development.

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