Cystic cerebellar dysplasia and biallelic LAMA1 mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects.
Laminins are heterotrimeric complexes, consisting of α, β and γ subunits that form a major component of basement membranes and extracellular matrix. Laminin complexes have different, but often overlapping, distributions and functions.



Under our clinical protocol, NCT00068224, we have performed extensive clinical and neuropsychiatric phenotyping, neuroimaging and molecular analysis in patients with laminin α1 (LAMA1)-associated lamininopathy. We investigated the consequence of mutations in LAMA1 using patient-derived fibroblasts and neuronal cells derived from neuronal stem cells.



In this paper we describe individuals with biallelic mutations in LAMA1, all of whom had the cerebellar dysplasia, myopia and retinal dystrophy, in addition to obsessive compulsive traits, tics and anxiety. Patient-derived fibroblasts have impaired adhesion, reduced migration, abnormal morphology and increased apoptosis due to impaired activation of Cdc42, a member of the Rho family of GTPases that is involved in cytoskeletal dynamics. LAMA1 knockdown in human neuronal cells also showed abnormal morphology and filopodia formation, supporting the importance of LAMA1 in neuronal migration, and marking these cells potentially useful tools for disease modelling and therapeutic target discovery.



This paper broadens the phenotypes associated with LAMA1 mutations. We demonstrate that LAMA1 deficiency can lead to alteration in cytoskeletal dynamics, which may invariably lead to alteration in dendrite growth and axonal formation. Estimation of disease prevalence based on population studies in LAMA1 reveals a prevalence of 1-20 in 1 000 000.



NCT00068224.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, Virginia, USA.
Thierry
T
Vilboux
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA NIH Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, Maryland, USA.
May Christine V
MC
Malicdan
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Yun Min
YM
Chang
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Jennifer
J
Guo
Diagnostic and Research Services Branch, Office of Research Services, National Institutes of Health, Bethesda, Maryland, USA.
Patricia M
PM
Zerfas
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Joshi
J
Stephen
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Department of Anatomy, College of Medicine, Howard University, Washington DC, USA.
Andrew R
AR
Cullinane
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Joy
J
Bryant
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Roxanne
R
Fischer
Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
Brian P
BP
Brooks
Ophthalmic Genetics & Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
Wadih M
WM
Zein
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Edythe A
EA
Wiggs
Audiology Unit, Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland, USA.
Christopher K
CK
Zalewski
Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, USA.
Andrea
A
Poretti
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Melanie M
MM
Bryan
NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Meghana
M
Vemulapalli
NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
James C
JC
Mullikin
Flow Cytometry Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Martha
M
Kirby
Flow Cytometry Core, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Stacie M
SM
Anderson
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Marjan
M
Huizing
NIH Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, Maryland, USA.
Camilo
C
Toro
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA NIH Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, Maryland, USA National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
William A
WA
Gahl
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Meral
M
Gunay-Aygun
D000328:Adult; D002448:Cell Adhesion; D002465:Cell Movement; D002526:Cerebellar Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002648:Child; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007797:Laminin / Q000235:genetics*; D008297:Male; D009154:Mutation; D009216:Myopia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009771:Obsessive-Compulsive Disorder / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D010375:Pedigree; D058499:Retinal Dystrophies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013577:Syndrome; D013981:Tic Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D055815:Young Adult; D020764:cdc42 GTP-Binding Protein
D007797:Laminin; C084098:laminin A; D020764:cdc42 GTP-Binding Protein
Clinical genetics; Genetics; Movement disorders (other than Parkinsons); Myopia; Neurosciences