Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9

Blood. 2015 Dec 17;126(25):2734-8. doi: 10.1182/blood-2015-09-659854.

Klaus Schmitz-Abe ¹, Szymon J Ciesielski ², Paul J Schmidt ³, Dean R Campagna ⁴, Fedik Rahimov ¹, Brenda A Schilke ², Marloes Cuijpers ⁵, Klaus Rieneck ⁶, Birgitte Lausen ⁷, Michael L Linenberger ⁸, Anoop K Sendamarai ³, Chaoshe Guo ³, Inga Hofmann ⁹, Peter E Newburger ¹⁰, Dana Matthews ¹¹, Akiko Shimamura ¹¹, Pieter J L M Snijders ¹², Meghan C Towne ¹³, Charlotte M Niemeyer ¹⁴, Henry G Watson ¹⁵, Morten H Dziegiel ⁶, Matthew M Heeney ⁹, Alison May ¹⁶, Sylvia S Bottomley ¹⁷, Dorine W Swinkels ¹⁸, Kyriacos Markianos ¹, Elizabeth A Craig ², Mark D Fleming ³

Affiliations

1 Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA;
2 Department of Biochemistry, University of Wisconsin, Madison, WI;
3 Harvard Medical School, Boston, MA; Department of Pathology, Boston Children's Hospital, Boston, MA;
4 Department of Pathology, Boston Children's Hospital, Boston, MA;
5 Department of Internal Medicine, Viecuri Medical Centre, Venlo, The Netherlands;
6 Department of Clinical Immunology, and.
7 Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;
8 Division of Hematology, University of Washington, Seattle, WA;
9 Harvard Medical School, Boston, MA; Department of Pediatrics, Dana-Farber Cancer Institute-Boston Children's Center for Cancer and Blood Disorders, Boston, MA;
10 Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA;
11 Division of Hematology, Seattle Children's Hospital, Seattle, WA;
12 Huisartsenteam Sint Willebrord, Sint Willebrord, The Netherlands;
13 Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA;
14 Pediatric Hematology and Oncology Department, Children's Hospital, University of Freiburg, Freiburg, Germany;
15 Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, Scotland;
16 Department of Haematology, Cardiff University School of Medicine, Heath Park, Cardiff, Wales;
17 Department of Medicine, Hematology-Oncology Section, University of Oklahoma College of Medicine, Oklahoma City, OK; and.
18 Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, Nijmegen, The Netherlands.

PMID: 26491070 DOI: 10.1182/blood-2015-09-659854

Abstract

The congenital sideroblastic anemias (CSAs) are relatively uncommon diseases characterized by defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Here we demonstrate that mutations in HSPA9, a mitochondrial HSP70 homolog located in the chromosome 5q deletion syndrome 5q33 critical deletion interval and involved in mitochondrial Fe-S biogenesis, result in CSA inherited as an autosomal recessive trait. In a fraction of patients with just 1 severe loss-of-function allele, expression of the clinical phenotype is associated with a common coding single nucleotide polymorphism in trans that correlates with reduced messenger RNA expression and results in a pseudodominant pattern of inheritance.

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