NBAS mutations cause a multisystem disorder involving bone, connective tissue, liver, immune system, and retina

Abstract

We report two unrelated patients with a multisystem disease involving liver, eye, immune system, connective tissue, and bone, caused by biallelic mutations in the neuroblastoma amplified sequence (NBAS) gene. Both presented as infants with recurrent episodes triggered by fever with vomiting, dehydration, and elevated transaminases. They had frequent infections, hypogammaglobulinemia, reduced natural killer cells, and the Pelger-Huët anomaly of their granulocytes. Their facial features were similar with a pointed chin and proptosis; loose skin and reduced subcutaneous fat gave them a progeroid appearance. Skeletal features included short stature, slender bones, epiphyseal dysplasia with multiple phalangeal pseudo-epiphyses, and small C1-C2 vertebrae causing cervical instability and myelopathy. Retinal dystrophy and optic atrophy were present in one patient. NBAS is a component of the synthaxin-18 complex and is involved in nonsense-mediated mRNA decay control. Putative loss-of-function mutations in NBAS are already known to cause disease in humans. A specific founder mutation has been associated with short stature, optic nerve atrophy and Pelger-Huët anomaly of granulocytes (SOPH) in the Siberian Yakut population. A more recent report associates NBAS mutations with recurrent acute liver failure in infancy in a group of patients of European descent. Our observations indicate that the phenotypic spectrum of NBAS deficiency is wider than previously known and includes skeletal, hepatic, metabolic, and immunologic aspects. Early recognition of the skeletal phenotype is important for preventive management of cervical instability.

Novel NBAS mutations and fever-related recurrent acute liver failure in Chinese children: a retrospective study

“…With this report, 23 NBAS -disease children with recurrent liver crises are described: 14 from European countries [12, 14, 19], 3 from the United States [12, 14], 3 from Lebanon (siblings; parental consanguinity known) [13], and our 3 Han Chinese. These patients’ phenotypes range from isolated RALF to RALF in association with multisystemic disease.…”

“…NBAS was previously linked to SOPH (short stature, optic nerve atrophy, and Pelger–Huët anomaly of granulocytes; MIM614800) syndrome in an isolated Russian Yakut population, but without liver failure [11]. Further observations expanded the phenotype spectrum of NBAS disease to involve brain, connective tissues other than bone, and the immune system as well [12–15]. …”

COPII-dependent ER export in animal cells: adaptation and control for diverse cargo

“…This mode of action is inextricably linked to the formation of rings of TANGO1 at ERES (Liu et al 2017; Raote et al 2017). NBAS mutations in humans cause multisystem disorders (Segarra et al 2015) that do include defects in bone formation (Balasubramanian et al 2017) and can therefore be linked to impaired procollagen transport.…”

NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype–phenotype correlations

“…So far, 47 different pathogenic NBAS variants have been reported in 71 individuals. To explore possible genotype–phenotype correlations, the available clinical data were collected (Table S5; Balasubramanian et al, ; Capo‐Chichi et al, ; Kortum et al, ; Maksimova et al, ; Megarbane et al, ; Regateiro et al, ; Segarra et al, ; Staufner et al, ; E‐P03.292008: European Society of Human Genetics 2018 meeting). A total of 36 patients have been reported to carry the homozygous p.Arg1914His change associated with the SOPH phenotype (Maksimova et al, ; Park & Lee, ), while two patients were reported to have a skeletal phenotype associated with the homozygous c.6237−3C>G splice‐site change (Palagano et al, ; Prontera et al, ).…”