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

Abstract

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.

Inherited Motor Neuron Disease in Domestic Cats: A Model of Spinal Muscular Atrophy

“…604320) of humans (23,24). However, the feline IGHMBP2 locus was excluded as the feline SMA gene by the same approach of intragenic marker development and linkage analysis demonstrated in this report (Q.H.…”

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

“…Intriguingly, senataxin itself is mutated in a juvenile-onset form of ALS, designated ALS4, that bears a striking resemblance to SMA and results in loss of motor neurons in early childhood (59). An additional RNA:DNA helicase, IGHMBP2, was initially characterized in the context of R-loop-dependent class-switch recombination, but it has since been found that loss-of-function mutations in IGHMBP2 cause spinal muscular atrophy type I with respiratory distress (60,61). These two independent lines of genetic evidence, in addition to our results, provide strong support for the causative role of unresolved R-loops in motor neuron disease.…”

Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits

“…A variant was considered to have musculoskeletal implications if (1) it is located within 100 kb or if it is an eQTL for a gene that has a relevant OMIM annotation, including association with human syndromes and animal models of relevant gene knock-outs, [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83] such as abnormal skeletal, muscle, or cartilage development and abnormal body size or bone morphology, and (2) there are any skeletalrelated GWAS signals within 100 kb, such as bone mineral density. For example, rs35863206 (WEAF 22.35%, beta ¼ À0.0232, height p ¼ 5.91 3 10 À9 ) is a deletion located 53 kb upstream of PGR, which encodes the progesterone receptor protein and is correlated with rs147581469 (r 2 ¼ 0.72), a previously identified eQTL for PGR.…”