PT  - JOURNAL ARTICLE
AU  - Thierry Vilboux
AU  - May Christine V Malicdan
AU  - Yun Min Chang
AU  - Jennifer Guo
AU  - Patricia M Zerfas
AU  - Joshi Stephen
AU  - Andrew R Cullinane
AU  - Joy Bryant
AU  - Roxanne Fischer
AU  - Brian P Brooks
AU  - Wadih M Zein
AU  - Edythe A Wiggs
AU  - Christopher K Zalewski
AU  - Andrea Poretti
AU  - Melanie M Bryan
AU  - Meghana Vemulapalli
AU  - James C Mullikin
AU  - Martha Kirby
AU  - Stacie M Anderson
AU  - NISC Comparative Sequencing Program
AU  - Marjan Huizing
AU  - Camilo Toro
AU  - William A Gahl
AU  - Meral Gunay-Aygun
TI  - Cystic cerebellar dysplasia and biallelic <em>LAMA1</em> mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects
AID  - 10.1136/jmedgenet-2015-103416
DP  - 2016 May 01
TA  - Journal of Medical Genetics
PG  - 318--329
VI  - 53
IP  - 5
4099  - http://jmg.bmj.com/content/53/5/318.short
4100  - http://jmg.bmj.com/content/53/5/318.full
SO  - J Med Genet2016 May 01; 53
AB  - 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