RT Journal Article SR Electronic T1 Cystic cerebellar dysplasia and biallelic LAMA1 mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 318 OP 329 DO 10.1136/jmedgenet-2015-103416 VO 53 IS 5 A1 Thierry Vilboux A1 May Christine V Malicdan A1 Yun Min Chang A1 Jennifer Guo A1 Patricia M Zerfas A1 Joshi Stephen A1 Andrew R Cullinane A1 Joy Bryant A1 Roxanne Fischer A1 Brian P Brooks A1 Wadih M Zein A1 Edythe A Wiggs A1 Christopher K Zalewski A1 Andrea Poretti A1 Melanie M Bryan A1 Meghana Vemulapalli A1 James C Mullikin A1 Martha Kirby A1 Stacie M Anderson A1 NISC Comparative Sequencing Program A1 Marjan Huizing A1 Camilo Toro A1 William A Gahl A1 Meral Gunay-Aygun YR 2016 UL http://jmg.bmj.com/content/53/5/318.abstract 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