Mutations In IGHMBP2 Research Articles

A congenital myopathy with diaphragmatic weakness not linked to the SMARD1 locus

Severe diaphragmatic weakness in infancy is rare. Common causes include structural myopathies, neuromuscular transmission defects, or anterior horn cell dysfunction (spinal muscular atrophy with respiratory distress, SMARD1). We describe a form of infantile diaphragmatic weakness without mutations in the SMARD1 gene, in which pathological and clinical features differ from known conditions, and investigations suggest a myopathy. We identified seven cases in four families. All presented soon after birth with feeding and breathing difficulties, marked head lag, facial weakness, and preserved antigravity movements in the limbs, with arms weaker than legs. All had paradoxical breathing and paralysis of at least one hemi-diaphragm. All required gastrostomy feeding, and all became ventilator-dependent. Investigations included myopathic EMG, muscle biopsy showing myopathic changes, normal electrophysiology and no mutations in SMN1 or IGHMBP2. These seven infants are affected by a myopathic condition clinically resembling SMARD1. However, its pathogenesis appears to be a myopathy affecting predominantly the diaphragm.

Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD): defining novel phenotypes through hierarchical cluster analysis

Autosomal recessive spinal muscular atrophy with respiratory distress (SMARD) is a heterogeneous disorder. Mutations in the immunoglobulin micro-binding protein gene (IGHMBP2) lead to SMARD1, but clinical criteria that delineate SMARD1 from other SMARD syndromes are not well established. Here we present a retrospective clinical and genetic study to determine the criteria that would predict the presence or absence of IGHMBP2 mutations. From 141 patients with respiratory distress and a spinal muscular atrophy phenotype we recorded the clinical features through a questionnaire and sequenced the entire coding region of IGHMBP2. In 47 (33%) patients we identified IGHMBP2 mutations, 14 of which were not described before. Clinical features and combinations thereof associated with the presence of IGHMBP2 mutations were discovered through hierarchical cluster analysis. This method detects common traits not evident at first sight by grouping items according to their similarity. The combination of "manifestation of respiratory failure between 6 weeks and 6 months" AND ("presence of diaphragmatic eventration" OR "preterm birth") predicted the presence of IGHMBP2 mutations with 98% sensitivity and 92% specificity. Non-SMARD1 patients fell into two different symptom clusters, mainly separated by the age at respiratory failure and the presence of multiple congenital contractures. The 14 novel IGHMBP2 mutations comprised missense, frameshift, splice-site, and nonsense mutations. All missense mutations altered conserved residues within or adjacent to the putative DNA helicase domain. The c.1235+3A>G splice-site mutation did not entirely suppress correct splicing and we found a residual wild-type IGHMBP2 mRNA steady-state level of 24.4+/-6.9%, which was, however, not sufficient to avert SMARD1 in this patient.

Allelic heterogeneity of SMARD1 at the IGHMBP2 locus.

Spinal Muscular Atrophy with Respiratory Distress (SMARD) is an autosomal recessive disorder characterized by neurogenic muscular atrophy due to progressive anterior horn cell degeneration and early life-threatening respiratory failure ascribed to diaphragmatic dysfunction. SMARD is clinically and genetically heterogeneous. SMARD type 1 is characterized by onset of respiratory failure within the first weeks of life and has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We report here the identification of nine novel IGHMBP2 mutations in five SMARD1 patients, including seven missense [ c.587A>G (p.Gln196Arg), c.647C>T (p.Pro216Leu), c.752T>C (p.Leu251Pro), c.1693G>A (p.Asp565Asn), c.1730T>C (p.Leu577Pro), c.1807C>T (p.Arg603Cys), c.1909C>T (p.Arg637Cys)] and two nonsense mutations [ c.1488C>A (p.Cys496X), c.2368C>T (p.Arg790X)]. Interestingly, 7 of 9 mutations occurred at highly conserved residues of the putative DNA helicase domain. The identification of novel IGHMBP2 variants will hopefully help diagnosing SMARD1 and contribute to a better functional characterization of IGHMBP2 gene product.

Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1.

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.