Cystic cerebellar dysplasia and biallelic LAMA1 mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects
Thierry Vilboux, May Christine V Malicdan, Yun Min Chang, Jennifer Guo, Patricia M Zerfas, Joshi Stephen, Andrew R Cullinane, Joy Bryant, Roxanne Fischer, Brian P Brooks, Wadih M Zein, Edythe A Wiggs, Christopher K Zalewski, Andrea Poretti, Melanie M Bryan, Meghana Vemulapalli, James C Mullikin, Martha Kirby, Stacie M Anderson, NISC Comparative Sequencing Program, Marjan Huizing, Camilo Toro, William A Gahl, Meral Gunay-Aygun, Thierry Vilboux, May Christine V Malicdan, Yun Min Chang, Jennifer Guo, Patricia M Zerfas, Joshi Stephen, Andrew R Cullinane, Joy Bryant, Roxanne Fischer, Brian P Brooks, Wadih M Zein, Edythe A Wiggs, Christopher K Zalewski, Andrea Poretti, Melanie M Bryan, Meghana Vemulapalli, James C Mullikin, Martha Kirby, Stacie M Anderson, NISC Comparative Sequencing Program, Marjan Huizing, Camilo Toro, William A Gahl, Meral Gunay-Aygun
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Trial registration number: NCT00068224.
Keywords: Clinical genetics; Genetics; Movement disorders (other than Parkinsons); Myopia; Neurosciences.
Conflict of interest statement
Competing interests None declared.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Figures
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LAMA1 deficiency disrupts cell architecture…
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LAMA1 deficiency disrupts cell architecture for focal adhesion in fibroblasts. Equal numbers of…
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Effects of LAMA1 knockdown in…
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Effects of LAMA1 knockdown in neuronal cells (A–C); LAMA1 knockdown in neuronal cells…
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- Case Reports
- Research Support, N.I.H., Intramural
- Adult
- Cell Adhesion
- Cell Movement
- Cerebellar Diseases / genetics
- Cerebellar Diseases / metabolism*
- Cerebellar Diseases / physiopathology
- Child
- Female
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- Fibroblasts / physiology
- Humans
- Laminin / genetics*
- Male
- Mutation*
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- Neurons / metabolism
- Neurons / physiology
- Obsessive-Compulsive Disorder / genetics
- Obsessive-Compulsive Disorder / metabolism*
- Obsessive-Compulsive Disorder / physiopathology
- Pedigree
- Retinal Dystrophies / genetics
- Retinal Dystrophies / metabolism
- Retinal Dystrophies / physiopathology
- Syndrome
- Tic Disorders / genetics
- Tic Disorders / metabolism
- Tic Disorders / physiopathology
- Young Adult
- cdc42 GTP-Binding Protein
- Laminin
- laminin A
- cdc42 GTP-Binding Protein
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![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8378307/bin/nihms-1728323-f0004.jpg)
Figure 5
Effects of LAMA1 knockdown in…
Figure 5
Effects of LAMA1 knockdown in neuronal cells (A–C); LAMA1 knockdown in neuronal cells…
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8378307/bin/nihms-1728323-f0005.jpg)
Source: PubMed