Clinical and functional spectrum of RAC2-related immunodeficiency.

ABSTRACT: Mutations in the small Rho-family guanosine triphosphate hydrolase RAC2, critical for actin cytoskeleton remodeling and intracellular signal transduction, are associated with neonatal severe combined immunodeficiency (SCID), infantile neutrophilic disorder resembling leukocyte adhesion deficiency (LAD), and later-onset combined immune deficiency (CID). We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity. Data were collected from referring physicians and literature reports with updated clinical information. Patients were grouped by presentation: neonatal SCID (n = 5), infantile LAD-like disease (n = 5), or CID (n = 44). Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID. Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients; myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes. Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common. Twenty-three distinct RAC2 mutations, including 15 novel variants, were identified. Using heterologous expression systems, we assessed downstream effector functions including superoxide production, p21-activated kinase 1 binding, AKT activation, and protein stability. Confocal microscopy showed altered actin assembly evidenced by membrane ruffling and macropinosomes. Altered protein localization and aggregation were observed. All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence. Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections. RAC2 mutations cause a spectrum of immune dysfunction, ranging from early onset SCID to later-onset combined immunodeficiencies depending on RAC2 activity. This trial was registered at www.clinicaltrials.gov as #NCT00001355 and #NCT00001467.

Imerslund-Gräsbeck syndrome in a 15-year-old German girl caused by compound heterozygous mutations in CUBN.

Imerslund-Gräsbeck syndrome (IGS) is a recessive disorder of intestinal cobalamin (Cbl) absorption and renal tubular protein reabsorption sometimes accompanied by urinary tract malformation. Mutations in the cubilin (CUBN) and amnionless (AMN) genes have been described as causal defects. CUBN and AMN proteins form the cubam complex that functions as the receptor for the intrinsic factor-Cbl (IF-Cbl) complex in the ileum and for proteins found in the primary urine in the kidney. We report the case of a 15-year-old German girl who presented with megaloblastic anaemia and funicular myelosis due to Cbl-deficiency and selective proteinuria. We clinically diagnosed- and for the first time in a patient of German ancestry-genetically confirmed IGS by detecting a compound heterozygous gene deletion and missense mutation in the CUBN gene. In conclusion IGS should be considered in paediatric patients presenting with symptoms like megaloblastic anaemia, funicular myelosis and benign proteinuria. Diagnosis should be confirmed genetically to avoid further invasive diagnostics, administer proper lifelong treatment and offer genetic counselling.