Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome

详细信息    查看全文

• 作者：Machteld M. Oud¹ ; ²⁶ ; ^{machteld.oud@radboudumc.nl} ; Paul Tuijnenburg² ; ³ ; ²⁶ ; Maja Hempel⁴ ; ²⁶ ; Naomi van Vlies⁵ ; Zemin Ren⁶ ; Sacha Ferdinandusse⁵ ; Machiel H. Jansen² ; ³ ; René ; Santer⁷ ; Jessika Johannsen⁷ ; Chiara Bacchelli⁸ ; Marielle Alders⁹ ; Rui Li¹⁰ ; ¹¹ ; Rosalind Davies⁸ ; Lucie Dupuis¹² ; Catherine M. Cale¹³ ; Ronald J.A. Wanders⁵ ; Steven T. Pals⁶ ; Louise Ocaka⁸ ; Chela James⁸ ; Ingo Mü ; ller¹⁴ ; Kai Lehmberg¹⁴ ; Tim Strom¹⁵ ; ¹⁶ ; Hartmut Engels¹⁷ ; Hywel J. Williams⁸ ; Phil Beales⁸ ; Ronald Roepman¹ ; Patricia Dias¹⁸ ; Han G. Brunner¹ ; Jan-Maarten Cobben¹⁹ ; ²⁰ ; Christine Hall²¹ ; Taila Hartley²² ; Polona Le Quesne Stabej⁸ ; Roberto Mendoza-Londono¹² ; E. Graham Davies⁸ ; ¹³ ; Sé ; rgio B. de Sousa⁸ ; ²³ ; ²⁴ ; Davor Lessel⁴ ; ²⁷ ; Heleen H. Arts¹ ; ²⁵ ; ²⁷ ; Taco W. Kuijpers² ; ²⁷ ; ^{t.w.kuijpers@amc.uva.nl}
• 关键词：exostosin ; EXTL3 ; T cell SCID ; heparan sulfate ; neuro-immuno-skeletal dysplasia
• 刊名：The American Journal of Human Genetics
• 出版年：2017
• 出版时间：2 February 2017
• 年：2017
• 卷：100
• 期：2
• 页码：281-296
• 全文大小：3177 K
• 卷排序：100

文摘

EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.