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A mutation affecting laminin alpha 5 polymerisation gives rise to a syndromic developmental disorder.
- Source :
-
Development (Cambridge, England) [Development] 2020 Jun 22; Vol. 147 (21). Date of Electronic Publication: 2020 Jun 22. - Publication Year :
- 2020
-
Abstract
- Laminin alpha 5 (LAMA5) is a member of a large family of proteins that trimerise and then polymerise to form a central component of all basement membranes. Consequently, the protein plays an instrumental role in shaping the normal development of the kidney, skin, neural tube, lung and limb, and many other organs and tissues. Pathogenic mutations in some laminins have been shown to cause a range of largely syndromic conditions affecting the competency of the basement membranes to which they contribute. We report the identification of a mutation in the polymerisation domain of LAMA5 in a patient with a complex syndromic disease characterised by defects in kidney, craniofacial and limb development, and by a range of other congenital defects. Using CRISPR-generated mouse models and biochemical assays, we demonstrate the pathogenicity of this variant, showing that the change results in a failure of the polymerisation of α/β/γ laminin trimers. Comparing these in vivo phenotypes with those apparent upon gene deletion in mice provides insights into the specific functional importance of laminin polymerisation during development and tissue homeostasis.<br />Competing Interests: Competing interestsA.J.M. has received research grant funding from Sanofi-Genzyme and has membership of an Advisory Board for Otsuka, neither of which are related to this project or work.<br /> (© 2020. Published by The Company of Biologists Ltd.)
- Subjects :
- Amino Acid Sequence
Animals
Animals, Newborn
Child, Preschool
Developmental Disabilities pathology
Fetus embryology
Humans
Hydronephrosis pathology
Infant, Newborn
Kidney abnormalities
Kidney embryology
Kidney pathology
Laminin chemistry
Lung abnormalities
Lung embryology
Lung pathology
Male
Mice
Protein Domains
Syndrome
Developmental Disabilities genetics
Fetal Development
Laminin genetics
Mutation genetics
Polymerization
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9129
- Volume :
- 147
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Development (Cambridge, England)
- Publication Type :
- Academic Journal
- Accession number :
- 32439764
- Full Text :
- https://doi.org/10.1242/dev.189183