A mutation affecting laminin alpha 5 polymerisation gives rise to a syndromic developmental disorder

Jones, Lynelle K., Lam, Rachel, McKee, Karen K., Aleksandrova, Maya, Dowling, John, Alexander, Stephen I., Mallawaarachchi, Amali, Cottle, Denny L., Short, Kieran M., Pais, Lynn, Miner, Jeffery H., Mallett, Andrew, Simons, Cas, McCarthy, Hugh, Yurchenco, Peter D., and Smyth, Ian M. (2020) A mutation affecting laminin alpha 5 polymerisation gives rise to a syndromic developmental disorder. Development, 147 (21). dev189183.

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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.

Item ID: 67856
Item Type: Article (Research - C1)
ISSN: 1477-9129
Keywords: Laminin alpha 5, LAMA5, Basement membrane, Kidney, Laminin polymerisation
Copyright Information: ©2020. Published by The Company of Biologists Ltd.
Funders: National Health and Medical Research Council (NHMRC)
Projects and Grants: NHMRC APP1098654, NHMRC APP1106516
Date Deposited: 06 Jul 2022 01:38
FoR Codes: 31 BIOLOGICAL SCIENCES > 3105 Genetics > 310507 Genetic immunology @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320214 Nephrology and urology @ 50%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 100%
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