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DOI 10.21203/rs.3.rs-4547888/v1

Медицинская библиотека · Research square · 2024

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

Gensemer Cortney, Beck Tyler, Guo Lilong, Petrucci Taylor, Morningstar Jordan, Kornblau Isabelle, Byerly Kathryn, Biggs Rachel, Weintraub Amy, Moore Kelsey, Koren Natalie, Daylor Victoria, Hastings Christina, Oberlies Emily, Zientara Ella R, Devey Elsie, Dooley Sarah, Stayer Kristina, Fenner Roman, Singleton Katherine, Luzbetak Sofia, Bear Deatra, Byrd Rebecca, Weninger Julianna, Bistran Erika, Beeson Gyda, Kerns Joshua, Griggs Molly, Griggs Charlotte, Osterhaus Madalyn, Fleck Emily, Schnaudigel Jillian, Butler Shaina, Severance Sydney, Kendall Wiley, Delaney Joe R, Judge Daniel P, Chen Peng, Yao Hai, Guz Jan, Awgulewitsch Alexander, Kautz Steven A, Mukherjee Rupak, Price Robert, Henderson Fraser, Shapiro Steven, Francomano Clair A, Kovacic Jason C, Lavallee Mark, Patel Sunil, Berrandou Takiy-Eddine, Slaugenhaupt Susan A, Milan David, Kontorovich Amy R, Bouatia-Naji Nabila, Norris Russell A

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Аннотация

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 G224D/+ 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.

Для цитирования: Gensemer Cortney, Beck Tyler, Guo Lilong, Petrucci Taylor, Morningstar Jordan, Kornblau Isabelle, Byerly Kathryn, Biggs Rachel, Weintraub Amy, Moore Kelsey, Koren Natalie, Daylor Victoria, Hastings Christina, Oberlies Emily, Zientara Ella R, Devey Elsie, Dooley Sarah, Stayer Kristina, Fenner Roman, Singleton Katherine, Luzbetak Sofia, Bear Deatra, Byrd Rebecca, Weninger Julianna, Bistran Erika, Beeson Gyda, Kerns Joshua, Griggs Molly, Griggs Charlotte, Osterhaus Madalyn, Fleck Emily, Schnaudigel Jillian, Butler Shaina, Severance Sydney, Kendall Wiley, Delaney Joe R, Judge Daniel P, Chen Peng, Yao Hai, Guz Jan, Awgulewitsch Alexander, Kautz Steven A, Mukherjee Rupak, Price Robert, Henderson Fraser, Shapiro Steven, Francomano Clair A, Kovacic Jason C, Lavallee Mark, Patel Sunil, Berrandou Takiy-Eddine, Slaugenhaupt Susan A, Milan David, Kontorovich Amy R, Bouatia-Naji Nabila, Norris Russell A. Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndrome.. Research square. 2024. DOI: 10.21203/rs.3.rs-4547888/v1.
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