Congenital sideroblastic anemia due to mutations in the mitochondrial HSP70 homologue HSPA9.
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.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA;
Klaus
K
Schmitz-Abe
Department of Biochemistry, University of Wisconsin, Madison, WI;
Szymon J
SJ
Ciesielski
Harvard Medical School, Boston, MA; Department of Pathology, Boston Children's Hospital, Boston, MA;
Paul J
PJ
Schmidt
Department of Pathology, Boston Children's Hospital, Boston, MA;
Dean R
DR
Campagna
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA;
Fedik
F
Rahimov
Department of Biochemistry, University of Wisconsin, Madison, WI;
Brenda A
BA
Schilke
Department of Internal Medicine, Viecuri Medical Centre, Venlo, The Netherlands;
Marloes
M
Cuijpers
Department of Clinical Immunology, and.
Klaus
K
Rieneck
Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;
Birgitte
B
Lausen
Division of Hematology, University of Washington, Seattle, WA;
Michael L
ML
Linenberger
Harvard Medical School, Boston, MA; Department of Pathology, Boston Children's Hospital, Boston, MA;
Anoop K
AK
Sendamarai
Harvard Medical School, Boston, MA; Department of Pathology, Boston Children's Hospital, Boston, MA;
Chaoshe
C
Guo
Harvard Medical School, Boston, MA; Department of Pediatrics, Dana-Farber Cancer Institute-Boston Children's Center for Cancer and Blood Disorders, Boston, MA;
Inga
I
Hofmann
Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA;
Peter E
PE
Newburger
Division of Hematology, Seattle Children's Hospital, Seattle, WA;
Dana
D
Matthews
Division of Hematology, Seattle Children's Hospital, Seattle, WA;
Akiko
A
Shimamura
Huisartsenteam Sint Willebrord, Sint Willebrord, The Netherlands;
Pieter J L M
PJ
Snijders
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA;
Meghan C
MC
Towne
Pediatric Hematology and Oncology Department, Children's Hospital, University of Freiburg, Freiburg, Germany;
Charlotte M
CM
Niemeyer
Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, Scotland;
Henry G
HG
Watson
Department of Clinical Immunology, and.
Morten H
MH
Dziegiel
Harvard Medical School, Boston, MA; Department of Pediatrics, Dana-Farber Cancer Institute-Boston Children's Center for Cancer and Blood Disorders, Boston, MA;
Matthew M
MM
Heeney
Department of Haematology, Cardiff University School of Medicine, Heath Park, Cardiff, Wales;
Alison
A
May
Department of Medicine, Hematology-Oncology Section, University of Oklahoma College of Medicine, Oklahoma City, OK; and.
Sylvia S
SS
Bottomley
Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Centre, Nijmegen, The Netherlands.
Dorine W
DW
Swinkels
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA;
Kyriacos
K
Markianos
Department of Biochemistry, University of Wisconsin, Madison, WI;
Elizabeth A
EA
Craig
Harvard Medical School, Boston, MA; Department of Pathology, Boston Children's Hospital, Boston, MA;
Mark D
MD
Fleming
D000328:Adult; D000368:Aged; D000756:Anemia, Sideroblastic / Q000235:genetics*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D005838:Genotype; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D018840:HSP70 Heat-Shock Proteins; C492001:HSPA9 protein, human; D024101:Mitochondrial Proteins