Rare LRRFIP1 variants contribute to pathophysiology of severe early-onset scoliosis and common scoliotic phenotypes.

Authors

Tanja Frey, Elena M Cabello, Gabriele Siegel, Carla Bello, Rike Schiller, Martina A Trippel, Neguin Ranjbar, Paranchai Boonsawat, Stephanie E van Gijn, Ivan Ivanovski, Michael Papik, Markus Zweier, Kan Min, Katharina Steindl, Anita Rauch

Published in

The Journal of clinical investigation. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

Despite enormous advances in clinical genomics, idiopathic scoliosis remains an enigmatic condition with poorly understood genetic and pathophysiological underpinnings impeding molecular diagnosis and the development of targeted treatments. We performed linkage analysis, exome, genome and short- and long-read RNA sequencing in a multigenerational family affected by autosomal dominant early-onset scoliosis (EOS) with a unique pattern of spondylodysplastic elements and progressive endplate erosion and identified the LRR binding FLII interacting protein 1 gene (LRRFIP1) as the disease-causing gene. The underlying cause is a rare noncoding variant altering transcription factor binding of NR3C1 (glucocorticoid receptor) leading to changes in LRRFIP1-isoform expression. Transcriptomic changes in fibroblasts of affected individuals indicated a combination of disturbed Wnt-signaling during somitogenesis, planar cell polarity signaling and postnatal inflammatory dysregulation with clinical and molecular overlaps with Ankylosing Spondylitis and Scheuermann kyphosis. We conducted a rare variant enrichment analysis using genome data from 484,903 UK Biobank participants and found an enrichment of rare risk-increasing LRRFIP1-variants in individuals with scoliosis. Our analysis of an Lrrfip1tm1.1(KOMP)Wtsi KO mouse model showed increased prevalence of idiopathic kyphoscoliosis in Lrrfip1-deficient mice. Our work provides insights into the pathophysiology of rare and common spinal disorders and hints to potential future therapeutic approaches with selective NR3C1-inhibitors.

PMID:
42809638
Bibliographic data and abstract were imported from PubMed on 30 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.