title: A novel HAX1 gene mutation in severe congenital neutropenia (SCN) associated with neurological manifestations.
abstract: Autosomal recessive severe congenital neutropenia (SCN) results from a maturation arrest of granulopoiesis at the level of promyelocytes and apoptosis of myeloid cells. In SCN patients, mutations have been described in the HAX1 gene. Most of the SCN patients who carry nonsense mutations that are common to both transcript variants of the HAX1 gene also exhibit neurological deficits. This study describes an SCN patient with neurological manifestations including daily episodes of atonic seizures, learning disabilities, and developmental delay. Sequencing of the HAX1 gene of this SCN patient identified a novel nonsense c.463_464insC homozygous mutation in exon 3, which is common to both transcript variants of the gene. This mutation encodes for a p.Gln155ProfsX14 change and causes premature truncation of the HAX1 protein. Neutrophils isolated from the patient exhibited spontaneous apoptosis and loss of inner mitochondrial membrane potential, which were further enhanced upon treatment with hydrogen peroxide. This study adds to the spectrum of novel HAX1 gene mutations and disease manifestations in ethnically distinct SCN patients. Our report describes the only nonsense mutation in the HAX1 gene present in SCN patients of Arab origin.
authors.affiliation: Department of Pathology and Laboratory Medicine, Molecular Genetics Laboratory, King Faisal Specialist Hospital & Research Centre, PO Box 3354, MBC#10, Riyadh 11211, Saudi Arabia. MFHaque@Kfshrc.edu.sa
authors.forename: Muhammad
authors.initials: M
authors.lastname: Faiyaz-Ul-Haque
authors.forename: Abdullah
authors.initials: A
authors.lastname: Al-Jefri
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.forename: Jalaluddin A K M
authors.initials: JA
authors.lastname: Bhuiyan
authors.forename: Hala A
authors.initials: HA
authors.lastname: Abalkhail
authors.forename: Randa
authors.initials: R
authors.lastname: Al-Nounou
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al-Abdullatif
authors.forename: Monogaran S
authors.initials: MS
authors.lastname: Pulicat
authors.forename: Ameera
authors.initials: A
authors.lastname: Gaafar
authors.forename: Ayodele A
authors.initials: AA
authors.lastname: Alaiya
authors.forename: Iskra
authors.initials: I
authors.lastname: Peltekova
authors.forename: Syed H E
authors.initials: SH
authors.lastname: Zaidi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017209:Apoptosis; D018912:Arabs / Q000235:genetics*; D002648:Child; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000208:ethnology / Q000209:etiology*; D004829:Epilepsy, Generalized / Q000208:ethnology / Q000209:etiology*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D009503:Neutropenia / Q000150:complications / Q000151:congenital* / Q000208:ethnology / Q000235:genetics*; D009504:Neutrophils / Q000378:metabolism; D010375:Pedigree; D012529:Saudi Arabia
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018389:Codon, Nonsense; C104759:HAX1 protein, human