Chondrodysplasia and Abnormal Joint Development Associated with Mutations in IMPAD1, Encoding the Golgi-Resident Nucleotide Phosphatase, gPAPP

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• 作者：Lisenka  ; E.L.M. Vissers¹ ; ¹⁰ ; Ekkehart Lausch² ; ¹⁰ ; Sheila Unger² ; ³ ; ¹⁰ ; Ana  ; Belinda Campos-Xavier⁴ ; Christian Gilissen¹ ; Antonio Rossi⁵ ; Marisol Del  ; Rosario¹ ; Hanka Venselaar⁶ ; Ute Knoll⁷ ; Sheela Nampoothiri⁸ ; Mohandas Nair⁹ ; Jü ; rgen Spranger² ; Han  ; G. Brunner¹ ; Luisa Bonaf&#xe9 ; ⁴ ; Joris  ; A. Veltman¹ ; Bernhard Zabel² ; Andrea Superti-Furga² ; ⁴ ; ^{asuperti@unil.ch"" rel=""nofollow}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：13 May 2011
• 年：2011
• 卷：88
• 期：5
• 页码：608-615
• 全文大小：954 K

文摘

We used whole-exome sequencing to study three individuals with a distinct condition characterized by short stature, chondrodysplasia with brachydactyly, congenital joint dislocations, cleft palate, and facial dysmorphism. Affected individuals carried homozygous missense mutations in IMPAD1, the gene coding for gPAPP, a Golgi-resident nucleotide phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the byproduct of sulfotransferase reactions, to AMP. The mutations affected residues in or adjacent to the phosphatase active site and are predicted to impair enzyme activity. A fourth unrelated patient was subsequently found to be homozygous for a premature termination codon in IMPAD1. Impad1 inactivation in mice has previously been shown to produce chondrodysplasia with abnormal joint formation and impaired proteoglycan sulfation. The human chondrodysplasia associated with gPAPP deficiency joins a growing number of skeletoarticular conditions associated with defective synthesis of sulfated proteoglycans, highlighting the importance of proteoglycans in the development of skeletal elements and joints.