Deciphering the complexity of IGHMBP2 mutations : respiratory deficits as prognostic indicators of lifespan
Authors:   , Ricardez Hernandez Sara Maria 
Published: September 2024

According to the National Institutes of Health (NIH), over 10,000 rare diseases have been identified, impacting approximately 1 in 10 individuals, totaling around 30 million people in the United States. Nearly 90 percent of neuromuscular diseases (NMDs) fall under the category of rare diseases. Despite their low prevalence, NMDs are collectively common conditions. NMDs encompass a diverse range of neurological disorders, constituting a significant contributor to mortality and lifelong disability in both children and adults. NMDs include 5q-spinal muscular atrophy (SMA), spinal muscular atrophy with respiratory distress type 1 (SMARD1), and Charcot Marie Tooth Type 2S (CMT2S). SMA is a motor neuron disease caused by autosomal recessive mutations in the survival motor neuron gene 1 (SMN1) [1]. SMA is one of the most common genetic causes of infant mortality, with an incidence of 1:10,000 [2]. Progressive muscle weakness begins proximally and develops distally with the initial sparing of the diaphragm. As the disease progresses, intercostal muscles become weak, leading to thoracoabdominal asynchrony, a bell-shaped chest, and, eventually, respiratory failure [3]. In contrast, mutations in the immunoglobulin µ-DNA binding protein 2 human gene (IGHMBP2) gene on Chromosome 11q13 give rise to two different autosomal recessive diseases, SMARD1 and CMT2S. The first cases of SMARD1 were described in 1974 [4]. However, these putative SMARD1 cases were thought to be unusual presentations of an unknown etiology causing the most acute type of SMA, Werdnig Hoffman disease (SMA type 1). SMARD1 is a devastating disease: patients present with respiratory distress 1-2 months after birth due to bilateral diaphragmatic weakness and eventration, while xiv progressive distal to proximal muscle defects were not apparent until 3-4 months of age [4]. Conversely, the milder axonal neuropathy, CMT2S, was not described until 2014, after exome sequencing of two English female patients diagnosed previously with CMT2 but with no identified mutation [5]. In this work, we characterize a novel model for CMT2S, Ighmbp2H922Y/H922Y, and the first compound heterozygous model of SMARD1, Ighmbp2D564N/H922Y. Our studies delve into the intricate role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S, revealing significant differences between mouse models with homozygous recessive and compound heterozygous mutations. The H922Y homozygous mice exhibited a normal lifespan and did not display respiratory deficiencies. Mild motor function defects emerged later in life, consistent with CMT2S disease progression. Notably, lifespan cohorts in D564N/H922Y mice exhibited three distinct groups, contrasting with H922Y homozygous mice, which showed no reduction in lifespan. A groundbreaking aspect of the research is the identification of early respiratory pathology as a critical predictor of lifespan within the D564N/H922Y survival cohorts, independent of limb pathology. Moreover, this study uniquely separates IGHMBP2 function in respiration from limb motor function, underscoring the significant improvement in lifespan and fitness by reducing respiratory deficits. The findings establish a direct correlation between IGHMBP2 biochemical activity and disease pathogenesis associated with patient mutations in humans and mice, advancing our understanding of IGHMBP2 function and its impact on disease progression.