PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment.
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.
Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.|CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.|European School of Molecular Medicine, SEMM, University of Milan, Italy.
Massimo
M
Zollo
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.
Mustafa
M
Ahmed
Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.|CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.|European School of Molecular Medicine, SEMM, University of Milan, Italy.
Veronica
V
Ferrucci
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Vincenzo
V
Salpietro
Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.|CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
Fatemeh
F
Asadzadeh
Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.|CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
Marianeve
M
Carotenuto
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.
Reza
R
Maroofian
Section of Ophthalmology and Neuroscience, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, UK.|National Genetic Centre, Directorate General of Royal Hospital, Ministry of Health, Muscat, Sultanate of Oman.
Ahmed
A
Al-Amri
Molecular Genetics, Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.
Royana
R
Singh
Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.|CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
Iolanda
I
Scognamiglio
Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.|Medical Genetics Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Majid
M
Mojarrad
Dipartimento di Medicina Molecolare e Biotecnologie Mediche DMMBM, Università di Napoli Federico II, Via Sergio Pansini 5, Naples, 80131, Italy.|CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
Luca
L
Musella
Dipartimento di Scienze Chimiche, Università Federico II, Naples, Italy.
Angela
A
Duilio
Dipartimento di Scienze Chimiche, Università Federico II, Naples, Italy.
Angela
A
Di Somma
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Ender
E
Karaca
National Genetic Centre, Directorate General of Royal Hospital, Ministry of Health, Muscat, Sultanate of Oman.
Anna
A
Rajab
Department of Biology, Sultan Qaboos University, PO Box 36, Post code 123, Sultanate of Oman.
Aisha
A
Al-Khayat
Molecular Genetics, Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.
Tribhuvan
T
Mohan Mohapatra
Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Atieh
A
Eslahi
Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.|Department of Pediatric Neurology, Ghaem Medical Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Zip Code- 9919991766, Iran.
Farah
F
Ashrafzadeh
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.
Lettie E
LE
Rawlins
Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.
Rajniti
R
Prasad
Molecular Genetics, Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.
Rashmi
R
Gupta
Molecular Genetics, Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.
Preeti
P
Kumari
Molecular Genetics, Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.|Department of Psychiatry, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.
Mona
M
Srivastava
CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.
Flora
F
Cozzolino
Molecular Genetics, Department of Anatomy, Institute of Medical Sciences, Banaras Hindu University, Varanasi -221005, UP, India.
Sunil
S
Kumar Rai
CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.|Dipartimento di Scienze Chimiche, Università Federico II, Naples, Italy.
Maria
M
Monti
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.
Gaurav V
GV
Harlalka
Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
Michael A
MA
Simpson
Department of Neuroradiology, St. George's Hospital, London, UK.
Philip
P
Rich
Department of Biology, Sultan Qaboos University, PO Box 36, Post code 123, Sultanate of Oman.
Fatema
F
Al-Salmi
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.|Department of Biology, Sultan Qaboos University, PO Box 36, Post code 123, Sultanate of Oman.|Genetics Research Centre, St. George's, University of London, London, SW17 0RE, UK.
Michael A
MA
Patton
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.
Barry A
BA
Chioza
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Stephanie
S
Efthymiou
Unit of Neuroradiology, Department of Biomedical Science and Morphological and Functional Images, University of Messina, Messina, Italy.
Francesca
F
Granata
Unit of Child Neurology and Psychiatry, Department of Human Pathology of the Adult and Developmental Age, University of Messina, Messina, Italy.
Gabriella
G
Di Rosa
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Sarah
S
Wiethoff
Unit of Neuromuscular disorders, IRCCS Oasi Maria SS Troina, Enna, Italy.
Eugenia
E
Borgione
Unit of Neuromuscular disorders, IRCCS Oasi Maria SS Troina, Enna, Italy.
Carmela
C
Scuderi
Department of Neuroradiology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
Kshitij
K
Mankad
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK.
Michael G
MG
Hanna
CEINGE Biotecnologie Avanzate, Via Gaetano Salvatore 486, Naples, Italy.|Dipartimento di Scienze Chimiche, Università Federico II, Naples, Italy.
Piero
P
Pucci
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
Henry
H
Houlden
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.|Texas Children's Hospital, Houston, TX 77030, USA.
James R
JR
Lupski
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.
Andrew H
AH
Crosby
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.
Emma L
EL
Baple
D000293:Adolescent; D001921:Brain / Q000254:growth & development*; D002352:Carrier Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002540:Cerebral Cortex / Q000254:growth & development; D002648:Child; D002675:Child, Preschool; D003599:Cytoskeleton / Q000235:genetics / Q000648:ultrastructure; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D008870:Microtubules / Q000235:genetics / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases; D055815:Young Adult
D002352:Carrier Proteins; C438732:PRUNE1 protein, human; D010744:Phosphoric Monoester Hydrolases
PRUNE1; developmental delay; microcephaly; microtubule polymerization, tubulinopathy; normal brain development