title: HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease).
abstract: Autosomal recessive severe congenital neutropenia (SCN) constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells, yet the underlying genetic defect remains unknown. Using a positional cloning approach and candidate gene evaluation, we identified a recurrent homozygous germline mutation in HAX1 in three pedigrees. After further molecular screening of individuals with SCN, we identified 19 additional affected individuals with homozygous HAX1 mutations, including three belonging to the original pedigree described by Kostmann. HAX1 encodes the mitochondrial protein HAX1, which has been assigned functions in signal transduction and cytoskeletal control. Here, we show that HAX1 is critical for maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells. Our findings suggest that HAX1 is a major regulator of myeloid homeostasis and underline the significance of genetic control of apoptosis in neutrophil development.
authors.affiliation: Department of Pediatric Hematology/Oncology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany. klein.christoph@mh-hannover.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Magda
authors.initials: M
authors.lastname: Grudzien
authors.forename: Giridharan
authors.initials: G
authors.lastname: Appaswamy
authors.forename: Manuela
authors.initials: M
authors.lastname: Germeshausen
authors.forename: Inga
authors.initials: I
authors.lastname: Sandrock
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.forename: Chozhavendan
authors.initials: C
authors.lastname: Rathinam
authors.forename: Kaan
authors.initials: K
authors.lastname: Boztug
authors.forename: Beate
authors.initials: B
authors.lastname: Schwinzer
authors.forename: Nima
authors.initials: N
authors.lastname: Rezaei
authors.forename: Georg
authors.initials: G
authors.lastname: Bohn
authors.forename: Malin
authors.initials: M
authors.lastname: Melin
authors.forename: Göran
authors.initials: G
authors.lastname: Carlsson
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
authors.forename: Jan
authors.initials: J
authors.lastname: Palmblad
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zeidler
authors.forename: Bodo
authors.initials: B
authors.lastname: Grimbacher
authors.forename: Karl
authors.initials: K
authors.lastname: Welte
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics*; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C104759:HAX1 protein, human; D011506:Proteins