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Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndrome.

Authors :
Gensemer C
Beck T
Guo L
Petrucci T
Morningstar J
Kornblau I
Byerly K
Biggs R
Weintraub A
Moore K
Koren N
Daylor V
Hastings C
Oberlies E
Zientara ER
Devey E
Dooley S
Stayer K
Fenner R
Singleton K
Luzbetak S
Bear D
Byrd R
Weninger J
Bistran E
Beeson G
Kerns J
Griggs M
Griggs C
Osterhaus M
Fleck E
Schnaudigel J
Butler S
Severance S
Kendall W
Delaney JR
Judge DP
Chen P
Yao H
Guz J
Awgulewitsch A
Kautz SA
Mukherjee R
Price R
Henderson F Sr
Shapiro S
Francomano CA
Kovacic JC
Lavallee M
Patel S
Berrandou TE
Slaugenhaupt SA
Milan D
Kontorovich AR
Bouatia-Naji N
Norris RA
Source :
Research square [Res Sq] 2024 Jun 10. Date of Electronic Publication: 2024 Jun 10.
Publication Year :
2024

Abstract

Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to hEDS, whole exome sequencing was performed on families and a cohort of sporadic hEDS patients. A missense variant in Kallikrein-15 (KLK15 p. Gly226Asp), segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the Kallikrein gene family. To validate pathogenicity, the variant identified in familial studies was used to generate knock-in mice. Consistent with our clinical cohort, Klk15 <superscript> G224D/+ </superscript> mice displayed structural and functional connective tissue defects within multiple organ systems. These findings support Kallikrein gene variants in the pathogenesis of hEDS and represent an important step towards earlier diagnosis and better clinical outcomes.

Details

Language :
English
ISSN :
2693-5015
Database :
MEDLINE
Journal :
Research square
Publication Type :
Academic Journal
Accession number :
38947032
Full Text :
https://doi.org/10.21203/rs.3.rs-4547888/v1