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Original article
Identification of the first dominant mutation of LAMA5 gene causing a complex multisystem syndrome due to dysfunction of the extracellular matrix
  1. Simone Sampaolo1,
  2. Filomena Napolitano2,
  3. Alfonsina Tirozzi3,
  4. Mafalda Giovanna Reccia3,
  5. Luca Lombardi1,
  6. Olimpia Farina1,
  7. Adriano Barra2,
  8. Ferdinando Cirillo4,
  9. Mariarosa Anna Beatrice Melone1,
  10. Fernando Gianfrancesco2,
  11. Giuseppe Di Iorio1,
  12. Teresa Esposito2,3
  1. 1 Neurology Clinic II and Reference Center for Rare Neuromuscular Disorders, Department of Medical Sciences, Surgery, Neurology, Metabolic Diseases and Geriatrics, Università degli Studi della Campania ’Luigi Vanvitelli', Naples, Italy
  2. 2 Institute of Genetics and Biophysics ’Adriano Buzzati-Traverso', National Research Council, Naples, Italy
  3. 3 IRCCS INM Neuromed, Pozzilli, Italy
  4. 4 Department of Clinical Medicine and Surgery, University of Naples ’Federico II', Naples, Italy
  1. Correspondence to Dr Teresa Esposito, Istituto di Genetica e Biofisica Adriano Buzzati Traverso,Consiglio Nazionale delle Ricerche, Via Pietro Castellino 111, 80131, Napoli, Italy.; teresa.esposito{at}


Background The laminin alpha 5 gene (LAMA5) plays a master role in the maintenance and function of the extracellular matrix (ECM) in mammalian tissues, which is critical in developmental patterning, stem cell niches, cancer and genetic diseases. Its mutations have never been reported in human disease so far. The aim of this study was to associate the first mutation in LAMA5 gene to a novel multisystem syndrome.

Methods A detailed characterisation of a three-generation family, including clinical, biochemical, instrumental and morphological analysis, together with genetics and expression (WES and RNAseq) studies, was performed.

Results The heterozygous LAMA5 mutation c.9418G>A (p.V3140M) was associated with skin anomalies, impaired scarring, night blindness, muscle weakness, osteoarthritis, joint and internal organs ligaments laxity, malabsorption syndrome and hypothyroidism. We demonstrated that the mutation alters the amount of LAMA5 peptides likely derived from protein cleavage and perturbs the activation of the epithelial-mesenchymal signalling, producing an unbalanced expression of Sonic hedgehog and GLI1, which are upregulated in cells from affected individuals, and of ECM proteins (COL1A1, MMP1 and MMP3), which are strongly inhibited. Studies carried out using human skin biopsies showed alteration of dermal papilla with a reduction of the germinative layer and an early arrest of hair follicle downgrowth. The knock-in mouse model, generated in our laboratory, shows similar changes in the tissues studied so far.

Conclusions This is the first report of a disease phenotype associated with LAMA5 mutation in humans.

  • laminin alpha 5 (LAMA5)gene
  • complex multisystem syndrome
  • extracellular matrix remodeling
  • whole exome sequencing (WES)
  • lama 5 knock-in.
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  • Contributors SS, FN, GDI and TE designed the study. SS, LL, OF, MABM and GDI recruited the family, performed clinical study and collected the data. FC performed the platelet study. TE and FG performed the analysis of WES and RNAseq data. FN performed the mutation analysis of the patients. FN, AT and MGR performed the RT-Q-PCR, immunofluorescence experiments and cellular studies. FN and TE made the mouse targeting molecule. FN, TE, SS and AB performed phenotype characterisation of the knock-in mouse model. SS, FN and TE wrote the manuscript. All authors revised the final manuscript.

  • Funding This work was supported in part by the Italian Association for Cancer Research (grant IG-2014 no.15707, FG).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Institutional Review Board (IRB) (Università degli Studi della Campania L Vanvitelli).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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