Inherited defects of the adipose tissue matrix and human metabolic disease

Sam M Lockhart; Yanislava Karusheva; Milan Muso; Joanne X Shen; John A Tadross; Brian Lam; Kara Rainbow; Yajie Zhao; Katherine Kentistou; Sofiya Gancheva; David Savage; Felix Day; John RB Perry; Ken K Ong; Larissa S. Athayde; Renan Montenegro Jr; Michael Roden; Stephen O

doi:10.1530/endoabs.115.OC6

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Endocrine Abstracts (2026) 115 OC6 | DOI: 10.1530/endoabs.115.OC6

IES2025 Oral Communications Oral Communications (14 abstracts)

Inherited defects of the adipose tissue matrix and human metabolic disease

Sam M Lockhart ^1,2,3 , Yanislava Karusheva ^4,5,6 , Milan Muso ¹ , Joanne X Shen ¹ , John A Tadross ¹ , Brian Lam ¹ , Kara Rainbow ¹ , Yajie Zhao ⁷ , Katherine Kentistou ⁷ , Sofiya Gancheva ^4,5,6 , David Savage ¹ , Felix Day ⁷ , John RB Perry ⁷ , Ken K Ong ⁷ , Larissa S. Athayde ⁸ , Renan Montenegro Jr ⁹ , Michael Roden ^4,5,6 & Stephen O’Rahilly ^1,2

Author affiliations

¹MRC Metabolic Diseases Unit, Institute of Metabolic Science, University of Cambridge, Cambridge; ²Wellcome-Wolfson Institute of Experimental Medicine. Queen’s University Belfast; ³Regional Center for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast Health and Social Care Trust; ⁴Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; ⁵German Center for Diabetes Research (DZD), München-Neuherberg, Germany; ⁶Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany; ⁷Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK; ⁸Universidade de São Paulo, Faculdade de Medicina, Departamento de Neurologia, Mendelics Genomic Analysis, São Paulo, Brazil; ⁹Clinical Research Unit, Walter Cantídio University Hospital, Federal University of Ceará/EBSERH, Fortaleza, Brazil

Mutations in genes encoding proteins of the extracellular matrix (ECM) result in several human disorders affecting tissues such as bone, skin, vasculature and skeletal muscle. To date, no such disorders principally affecting the ECM of adipose tissue have been reported. We now describe four patients from 3 unrelated consanguineous families in whom severe progressive partial lipodystrophy, severe insulin resistance and dyslipidaemia, is caused by homozygous loss of function mutations in LAMA 4, encoding an adipose tissue- enriched subunit of the abundant, trimeric, basement membrane protein, laminin. We used population genetics to demonstrate that ECM dysfunction contributes to adverse adiposity and metabolic dysfunction in the general population. In an analysis of over half a million participants in population biobanks heterozygous carriers of predicted loss of function mutations in three Collagen genes (COL5A3. COL; ³A1 and COL; ¹²A1), one matrix metalloproteinase ADAMTS 9 and the heparan sulphate proteoglycan gene HSPG 2, all of which are robustly expressed in adipose tissue, were associated with an increased waist-hip ratio (WHR) and a range of related metabolic dysfunctions. Across known GWAS loci for WHR, we find evidence of marked enrichment for ECM-related pathways. Thus, using evidence from a newly described monogenic syndrome and genetic variation across the allele frequency spectrum we demonstrate that adipose- enriched ECM genes contribute significantly to fat distribution and metabolic dysfunction in the general population. We propose the term “adipose matrixopathy” to describe this pathophysiologically distinct subclass of human metabolic disorder.