ADAMTSL2 – Geleophysic Dysplasia 1

Geleophysic dysplasia 1 is an autosomal recessive acromelic dysplasia marked by extreme short stature, brachydactyly, thickened skin and progressive cardiac valvular disease. ADAMTSL2 encodes an extracellular glycoprotein containing thrombospondin type-1 repeats and is essential for microfibril assembly and regulation of transforming growth factor-β (TGF-β) bioavailability.

Genetic evidence supports a definitively established association: biallelic ADAMTSL2 variants have been reported in 11 unrelated probands ([PMID:18677313]) with segregation in multiple families. Reported alleles include at least five missense, two splice-site, and three nonsense variants, consistent with a loss-of-function mechanism; a representative variant is c.340G>A (p.Glu114Lys).

Functional studies demonstrate that several disease-associated mutations reduce ADAMTSL2 secretion in HEK293 cells, leading to protein misfolding and enhanced TGF-β signaling (increased active TGF-β and nuclear phospho-SMAD2) ([PMID:18677313]). O-fucosylation assays showed that the p.Ser641Leu mutation abolishes TSR3 modification and impairs secretion ([PMID:32913123]). Adamtsl2–/– mice recapitulate bronchial epithelial dysplasia with microfibril accumulation and elevated TGF-β activity ([PMID:25762570]).

No studies have convincingly refuted this association. Inheritance is consistent with autosomal recessive transmission, and the phenotype is reproduced by both in vitro and in vivo loss-of-function models.

Overall, ADAMTSL2 meets criteria for a Definitive gene-disease association in geleophysic dysplasia 1, supporting its use in molecular diagnosis, genetic counseling, and development of targeted therapies.

Key Take-home: Loss-of-function ADAMTSL2 variants cause autosomal recessive geleophysic dysplasia 1 via impaired secretion and dysregulated TGF-β signaling, providing a robust diagnostic marker for this severe connective tissue disorder.

References

• Nature genetics • 2008 • ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta bioavailability regulation. PMID:18677313
• Pediatric and developmental pathology • 2014 • Novel mutations in geleophysic dysplasia type 1. PMID:24251637
• European journal of medical genetics • 2017 • A chinese boy with geleophysic dysplasia caused by compound heterozygous mutations in ADAMTSL2. PMID:28917829
• Molecular genetics and metabolism reports • 2019 • Geleophysic dysplasia: novel missense variants and insights into ADAMTSL2 intracellular trafficking. PMID:31516831
• The Journal of Biological Chemistry • 2020 • O-Fucosylation of ADAMTSL2 is required for secretion and is impacted by geleophysic dysplasia-causing mutations. PMID:32913123
• Disease models & mechanisms • 2015 • Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia--a novel mouse model providing insights into geleophysic dysplasia. PMID:25762570

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