Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

Abstract

Most patients with chronic granulomatous disease (CGD) have mutations in the X-linked CYBB gene that encodes gp91 phox , a component of the phagocyte NADPH oxidase. The resulting X-linked form of CGD is usually manifested in boys. Rarely, X-CGD is encountered in female carriers with extreme expression of the mutated gene. Here, we report on a woman with a novel mutation in CYBB (CCG [90][91][92] 3 GGT), predicting Tyr30Arg31 3 stop, Val in gp91 phox , who presented with clinical symptoms at the age of 66. The mutation was present in heterozygous form in genomic DNA from her leukocytes but was fully expressed in mRNA from these cells, indicating that in her leukocytes the X chromosome carrying the nonmutated CYBB allele had been inactivated. Indeed, only 0.4% to 2% of her neutrophils showed NADPH oxidase activity. This extreme skewing of her Xchromosome inactivation was not found in her cheek mucosal cells and is thus not due to a general defect in gene methylation on one X chromosome. Moreover, the CYBB mutation was not present in the DNA from her cheek cells and was barely detectable in the DNA from her memory T lymphocytes. Thus, this patient shows a somatic mosaic for the CYBB mutation, which probably originated during her lifetime in her bone marrow. IntroductionChronic granulomatous disease (CGD) is a rare, heterogeneous, inherited disorder that affects about 1 in 250 000 individuals. 1,2 The main defect in CGD is a failure of neutrophils, monocytes, macrophages, and eosinophils to mount a respiratory burst and, therefore, to generate superoxide anions and other reactive oxygen species derived from superoxide, such as hydrogen peroxide. This renders the patients susceptible to severe, recurrent bacterial and fungal infections. [3][4][5] The enzyme that generates superoxide is a phagocyte-specific nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, consisting of 2 membrane-bound subunits and 4 cytosolic proteins involved in activity regulation of the enzyme. 1,2 The central, catalytic subunit is gp91 phox , a flavocytochrome that forms a heterodimer with p22 phox in the plasma membrane of phagocytic leukocytes. Defects in gp91 phox are inherited in an X-linked fashion because its gene, CYBB, is located on the X chromosome. About 70% to 75% of the CGD patients are X-CGD patients. 1,2,6 Autosomal forms of CGD are due to mutations in CYBA, the gene that encodes p22 phox in approximately 3% of the CGD patients 6,7 or to mutations in the genes encoding the cytosolic proteins p47 phox (ϳ 25%) or p67 phox (ϳ 3%). 1,2,6 For many years the onset of CGD was regarded to occur early in infancy, with fatal outcome in adolescence, due to the recurrent severe infections and the secondary granulomatous and fibrotic tissue formation that develops in many organs. Changes frequently occur in the skin, lymph nodes, and lungs, but also in bones, joints, liver, and kidneys, leading eventually to pulmonary, gastrointestinal, musculoskeletal, and renal insufficiency. 1,2,5,8,9 In the last decades, with the rapid developme...

Redox modifier genes in amyotrophic lateral sclerosis in mice

“…Hence, in the absence of a selective bias, female mice heterozygous for these Nox genes would be expected to have 50% normal cells (with one active Nox gene) and 50% defective cells (with no active Nox gene). However, biased X chromosome inactivation has been previously reported in female patients with X-linked chronic granulomatous disease caused by Nox2 gene mutations (17). Given the significant protective effect seen in Nox2-HET female mice, we sought to determine how dosage of Nox2 activity in the spinal cord might influence disease progression in ALS mice.…”

Molecular epidemiology of chronic granulomatous disease in a series of 80 kindreds: identification of 31 novel mutations

“…Other symptomatic female carriers have been described in case reports, but often without specifying whether they had a de novo or inherited mutation (Cazzola et al, 1985;Romera-Modamio et al, 1997;Rosen-Wolff et al, 2001;Lun et al, 2002). Moreover, an E136 Kannengiesser et alunusual late presentation of X-linked CGD has been reported in an adult female with a somatic mosaic for a novel mutation in CYBB, which had probably originated during her lifetime in her bone marrow (Wolach et al, 2005). …”

Adult Onset X-Linked Chronic Granulomatous Disease in a Woman Patient Caused by a de novo Mutation in Paternal-Origin CYBB Gene and Skewed Inactivation of Normal Maternal X Chromosome

“…(6) (10). To date, the presence of adult onset X-linked CGD has been reported in only 3 woman patients (2)(3)(4). The precise mechanism by which the disease occurs in adults remains unclear but a positive correlation was observed between age and degree of skewing in X-inactivation (11).…”

“…For many years the onset of Xlinked CGD was thought to occur early in infancy in man patients, with a fatal outcome in adolescence due to recurrent severe bacterial or fungal infections. However, late onset cases of X-linked CGD have been recently reported in some adult woman (2)(3)(4). While it has been assumed that the late onset of woman X-linked CGD could be associated with age-related skewing of lyonization (2), the detailed mechanism of onset in adult woman patients remains obscure.…”