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.

HAX-1 regulates cyclophilin-D levels and mitochondria permeability transition pore in the heart

“…Studies in patients with HAX-1 mutation, exhibiting severe congenital neutropenia, showed that their neutrophils had low mitochondrial membrane potential compared with the healthy controls (16). However, elevated HAX-1 levels are associated with various types of cancer (8), where the mPTP activity can be inhibited for prosurvival purposes (33).…”

“…Importantly, human mutations in HAX-1 have been linked to mitochondrial function. These mutations, resulting in loss of protein or activity, were discovered in a subgroup of severe neutropenia patients (8,15,16) and they were associated with loss of mitochondrial membrane potential in the neutrophils of the human carriers (16). Thus, HAX-1 deficiency may cause a defect in the mitochondrial membrane.…”

Neurological findings and genetic alterations in patients with Kostmann syndrome and HAX1 mutations

“…The complete literature review (Table ), identified only 61 cases worldwide including our cases . The distribution of case is not ubiquitous.…”

“…Such results provide a molecular signature of the disease, which differentiates "Kostmann disease" from other types of congenital neutropenia. The complete literature review (Table I), identified only 61 cases worldwide including our cases [3][4][5][6][12][13][14][15][16][17][18][19][20][21][22][23][24]. The distribution of case is not ubiquitous.…”

Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project

“…Cyclic neutropenia (MIM 162800) is an autosomal dominant disease characterized by episodic neutropenia, also beginning in childhood. Variation at ELANE can cause both forms of neutropenia, and variation at other genes (e.g., GFI1, WAS, CXCR4, HAX1, and SDBS) causes SCN [Ancliff et al, 2006;Devriendt et al, 2001;Faiyaz-Ul-Haque et al, 2010;Germeshausen et al, 2007;Hauck and Klein 2013;Klein et al, 2007;Newburger and Dale, 2013;Person et al, 2003;Smith et al, 2009;Xia et al, 2009]. Individuals of African American (AA) ancestry and some other ethnic groups tend to have lower ANC than individuals with European American (EA) ancestry [Reiner et al, 2011].…”