Mutations in B3GALT6, which Encodes a Glycosaminoglycan Linker Region Enzyme, Cause a Spectrum of Skeletal and Connective Tissue Disorders

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• 作者：Masahiro Nakajima¹ ; ²¹ ; Shuji Mizumoto² ; ²¹ ; Noriko Miyake³ ; ²¹ ; Ryo Kogawa² ; Aritoshi Iida¹ ; Hironori Ito⁴ ; Hiroshi Kitoh⁵ ; Aya Hirayama⁶ ; Hiroshi Mitsubuchi⁷ ; Osamu Miyazaki⁸ ; Rika Kosaki⁹ ; Reiko Horikawa¹⁰ ; Angeline Lai¹¹ ; Roberto Mendoza-Londono¹² ; Lucie Dupuis¹² ; David Chitayat¹² ; Andrew Howard¹³ ; Gabriela F. Leal¹⁴ ; Denise Cavalcanti¹⁵ ; Yoshinori Tsurusaki³ ; Hirotomo Saitsu³ ; Shigehiko Watanabe¹⁶ ; Ekkehart Lausch¹⁷ ; Sheila Unger¹⁸ ; Luisa Bonafé ; ¹⁹ ; Hirofumi Ohashi¹⁶ ; Andrea Superti-Furga¹⁹ ; Naomichi Matsumoto³ ; Kazuyuki Sugahara² ; Gen Nishimura²⁰ ; Shiro Ikegawa¹ ; ^{sikegawa@ims.u-tokyo.ac.jp}
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：6 June, 2013
• 年：2013
• 卷：92
• 期：6
• 页码：927-934
• 全文大小：404 K

文摘

Proteoglycans (PGs) are a major component of the extracellular matrix in many tissues and function as structural and regulatory molecules. PGs are composed of core proteins and glycosaminoglycan (GAG) side chains. The biosynthesis of GAGs starts with the linker region that consists of four sugar residues and is followed by repeating disaccharide units. By exome sequencing, we found that B3GALT6 encoding an enzyme involved in the biosynthesis of the GAG linker region is responsible for a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1). B3GALT6 loss-of-function mutations were found in individuals with SEMD-JL1 from seven families. In a subsequent candidate gene study based on the phenotypic similarity, we found that B3GALT6 is also responsible for a connective tissue disease, Ehlers-Danlos syndrome (progeroid form). Recessive loss-of-function mutations in B3GALT6 result in a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation, and spinal deformity. The pleiotropic phenotypes of the disorders indicate that B3GALT6 plays a critical role in a wide range of biological processes in various tissues, including skin, bone, cartilage, tendon, and ligament.