Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans.
The combination of family-based linkage analysis with high-throughput sequencing is a powerful approach to identifying rare genetic variants that contribute to genetically heterogeneous syndromes. Using parametric multipoint linkage analysis and whole exome sequencing, we have identified a gene responsible for microcephaly (MCP), severe visual impairment, intellectual disability, and short stature through the mapping of a homozygous nonsense alteration in a multiply-affected consanguineous family. This gene, DIAPH1, encodes the mammalian Diaphanous-related formin (mDia1), a member of the diaphanous-related formin family of Rho effector proteins. Upon the activation of GTP-bound Rho, mDia1 generates linear actin filaments in the maintenance of polarity during adhesion, migration, and division in immune cells and neuroepithelial cells, and in driving tangential migration of cortical interneurons in the rodent. Here, we show that patients with a homozygous nonsense DIAPH1 alteration (p.Gln778*) have MCP as well as reduced height and weight. diap1 (mDia1 knockout (KO))-deficient mice have grossly normal body and brain size. However, our histological analysis of diap1 KO mouse coronal brain sections at early and postnatal stages shows unilateral ventricular enlargement, indicating that this mutant mouse shows both important similarities as well as differences with human pathology. We also found that mDia1 protein is expressed in human neuronal precursor cells during mitotic cell division and has a major impact in the regulation of spindle formation and cell division.
1] Child Study Center, Yale University School of Medicine, New Haven, CT, USA [2] Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.
A Gulhan
AG
Ercan-Sencicek
Al Hada Armed Hospitals, Taif, Saudi Arabia.
Samira
S
Jambi
Department of Neurobiology and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA.
Daniel
D
Franjic
1] Child Study Center, Yale University School of Medicine, New Haven, CT, USA [2] Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.
Sayoko
S
Nishimura
Department of Neurobiology and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA.
Mingfeng
M
Li
Child Study Center, Yale University School of Medicine, New Haven, CT, USA.
Paul
P
El-Fishawy
Department of Pediatrics, Vanderbilt University, Nashville, TN, USA.
Thomas M
TM
Morgan
Department of Psychiatry, University of California, School of Medicine, San Francisco, CA, USA.
Stephan J
SJ
Sanders
1] Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA [2] Yale Center for Mendelian Genomics, New Haven, CT, USA.
Kaya
K
Bilguvar
Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS, Trust City Hospital Campus, Nottingham, UK.
Mohnish
M
Suri
Departments of Diagnostic Radiology, Surgery and Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
Michele H
MH
Johnson
1] Child Study Center, Yale University School of Medicine, New Haven, CT, USA [2] Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
Abha R
AR
Gupta
Department of Medical Genetics, Osmangazi University, School of Medicine, Eskisehir, Turkey.
Zafer
Z
Yuksel
1] Yale Center for Mendelian Genomics, New Haven, CT, USA [2] Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Shrikant
S
Mane
1] Child Study Center, Yale University School of Medicine, New Haven, CT, USA [2] Moscow State University for Psychology and Education, Moscow, Russia.
Elena
E
Grigorenko
1] Child Study Center, Yale University School of Medicine, New Haven, CT, USA [2] Department of Neurobiology and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA [3] Departments of Psychiatry, Pharmocology Yale University School of Medicine, New Haven, CT, USA.
Marina
M
Picciotto
Laboratory of Cell Structure and Signal Integration, Van Andel Research Institute, Grand Rapids, MI, USA.
Arthur S
AS
Alberts
Department of Neurosurgery, Program on Neurogenetics, Yale School of Medicine, New Haven, CT, USA.
Murat
M
Gunel
Department of Neurobiology and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT, USA.
Nenad
N
Šestan
Department of Psychiatry, University of California, School of Medicine, San Francisco, CA, USA.
Matthew W
MW
State
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D005260:Female; D000080865:Formins; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018389:Codon, Nonsense; C108962:DIAPH1 protein, human; C491464:Diap1 protein, mouse; D000080865:Formins