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A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT

Peter M. Krawitz, Britta Höchsmann, Yoshiko Murakami, Britta Teubner, Ulrike Krüger, Eva Klopocki, Heidemarie Neitzel, Alexander Hoellein, Christina Schneider, Dmitri Parkhomchuk, Jochen Hecht, Peter N. Robinson, Stefan Mundlos, Taroh Kinoshita and Hubert Schrezenmeier

Key points

  • A carrier of a deleterious splice site mutation in PIGT acquired a second hit in PIGT and developed PNH.

Abstract

To ascertain the genetic basis of a PNH case without somatic mutations in PIGA, we performed deep next-generation sequencing on all exons of known genes of the GPI-anchor synthesis pathway. We identified a heterozygous germline splice site mutation in PIGT and a somatic 8MB deletion in granulocytes affecting the other copy of PIGT. PIGA is essential for GPI-anchor synthesis whereas PIGT is essential for attachment of preassembled GPI-anchor to proteins. While a single mutation event in the X-chromosomal gene PIGA is known to cause GPI-anchored protein deficiency, two such hits are required in the autosomal gene PIGT. Our data indicate that PNH can occur even in the presence of fully assembled GPI if its transfer to proteins is defective in hematopoietic stem cells.

  • Submitted January 28, 2013.
  • Accepted May 23, 2013.