Grohmann, K. et al. Mutations in the gene encoding immunoglobulin -binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat. Genet. 29, 75−77

Department of Neuropediatrics, Charité, Campus Virchow-Klinikum, Humboldt University, 13353 Berlin, Germany.
Nature Genetics (Impact Factor: 29.35). 10/2001; 29(1):75-7. DOI: 10.1038/ng703
Source: PubMed


Classic spinal muscular atrophy (SMA) is caused by mutations in the telomeric copy of SMN1. Its product is involved in various cellular processes, including cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins, pre-mRNA processing and activation of transcription. Spinal muscular atrophy with respiratory distress (SMARD) is clinically and genetically distinct from SMA. Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4). In six SMARD1 families, we detected three recessive missense mutations (exons 5, 11 and 12), two nonsense mutations (exons 2 and 5), one frameshift deletion (exon 5) and one splice donor-site mutation (intron 13). Mutations in mouse Ighmbp2 (ref. 14) have been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (nmd) mouse, whose phenotype resembles the SMARD1 phenotype. Like the SMN1 product, IGHMBP2 colocalizes with the RNA-processing machinery in both the cytoplasm and the nucleus. Our results show that IGHMBP2 is the second gene found to be defective in spinal muscular atrophy, and indicate that IGHMBP2 and SMN share common functions important for motor neuron maintenance and integrity in mammals.

1 Follower
23 Reads
  • Source
    • "SMARD1 is characterized by a sudden onset of respiratory distress, usually within the first year of life, with initially distal and later generalized muscle weakness (Eckart et al., 2012). SMARD1 results from mutations in the gene encoding the immunoglobulin microbinding protein 2 (IGHMBP2), which encodes an ATPase/helicase that belongs to the SF1 superfamily (Grohmann et al., 2001; Guenther et al., 2009; Jankowsky et al., 2011). A splice-site mutation in murine Ighmbp2 causes a neuromuscular disorder similar to the human disease in the nmd mouse, representing the animal model of SMARD1 (Cox et al., 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a motor neuron disease caused by mutations in the IGHMBP2 gene, without a cure. Here, we demonstrate that neural stem cells (NSCs) from human-induced pluripotent stem cells (iPSCs) have therapeutic potential in the context of SMARD1. We show that upon transplantation NSCs can appropriately engraft and differentiate in the spinal cord of SMARD1 animals, ameliorating their phenotype, by protecting their endogenous motor neurons. To evaluate the effect of NSCs in the context of human disease, we generated human SMARD1-iPSCs motor neurons that had a significantly reduced survival and axon length. Notably, the coculture with NSCs ameliorate these disease features, an effect attributable to the production of neurotrophic factors and their dual inhibition of GSK-3 and HGK kinases. Our data support the role of iPSC as SMARD1 disease model and their translational potential for therapies in motor neuron disorders.
    Full-text · Article · Aug 2014 · Stem Cell Reports
  • Source
    • "In addition, positional cloning technique reveals that the mutations in SETX gene in the locus also associated with autosomal recessive spinocerebellar ataxia-1 (SCAR1), which is also referred to ataxia-ocular apraxia-2 (AOA2) [19]. SETX gene encodes a ubiquitously expressed DNA/RNA helicase protein [19,20]. SETX and DNA/RNA helicases are involved in DNA repair, replication, recombination, transcription, RNA processing, transcript stability, and the initiation of translation [19,20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the devastating disease.
    Full-text · Article · Aug 2013 · Molecular Neurodegeneration
  • Source
    • "These pathological features correspond to motoneuron loss and muscle fiber degeneration, including myopathic changes which are prominent in the diaphragm (Diers et al., 2005; Grohmann et al., 2001; Rudnik- Schoneborn et al., 2004). As a monogenetic disorder, SMARD1 is caused by mutations in the IGHMBP2 (Immunoglobulin μ-binding protein 2) gene on chromosome 11q13 which codes for an ATPase/Helicase that belongs to the SF1 superfamily (Grohmann et al., 2001; Guenther et al., 2009a; Jankowsky, 2011). However, little is known about the impact of the described cell specific abnormalities on the disease phenotype and its progression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a childhood motoneuron disease caused by mutations in the gene encoding for IGHMBP2, an ATPase/Helicase. Paralysis of the diaphragm is an early and prominent clinical sign resulting both from denervation and myopathy. In skeletal muscles, muscle atrophy mainly results from loss of motoneuron cell bodies and axonal degeneration. Although it is well known that loss of motoneurons at the lumbar spinal cord is an early event in the pathogenesis of the disease, it is not clear whether the corresponding proximal axons and NMJs are also early affected. In order to address this question, we have investigated the time course of the disease progression at the level of the motoneuron cell body, proximal axon (ventral root), distal axon (sciatic nerve), NMJ, and muscle fiber in Nmd(2J) mice, a mouse model for SMARD1. Our results show an early and apparently parallel loss of motoneurons, proximal axons, and NMJs. In affected muscles, however, denervated fibers coexist with NMJs with normal morphology and unaltered neurotransmission. Furthermore, unaffected axons are able to sprout and reinnervate muscle fibers, suggesting selective vulnerability of neurons to Ighmbp2 deficiency. The preservation of the NMJ morphology and neurotransmission in the Nmd(2J) mouse until motor axon loss takes place, differs from that observed in SMA mouse models in which NMJ impairment is an early and more general phenomenon in affected muscles.
    Full-text · Article · Jan 2013 · Neurobiology of Disease
Show more