Clinical and molecular characteristics in three families with biallelic mutations in IGHMBP2

Abstract

Biallelic mutations in IGHMBP2 cause spinal muscular atrophy with respiratory distress type 1 (SMARD1) or Charcot-Marie-Tooth type 2S (CMT2S). We report three families variably affected by IGHMBP2 mutations. Patient 1, an 8-year-old boy with two homozygous variants: c.2T>C and c.861C>G, was wheelchair bound due to sensorimotor axonal neuropathy and chronic respiratory failure. Patient 2 and his younger sister, Patient 3, had compound heterozygous variants: c.983_987delAAGAA and c.1478C>T. However, clinical phenotypes differed markedly as the elder with sensorimotor axonal neuropathy had still unaffected respiratory function at 4.5 years, whereas the younger presented as infantile spinal muscular atrophy and died from relentless respiratory failure at 11 months. Patient 4, a 6-year-old girl homozygous for IGHMBP2 c.449+1G>T documented to result in two aberrant transcripts, was wheelchair dependent due to axonal polyneuropathy. The clinical presentation in Patients 1 and 3 were consistent with SMARD1, whereas Patients 2 and 4 were in agreement with CMT2S.

UPF1-like helicase grip on nucleic acids dictates processivity

“…As UPF1 is the prototype of the UPF1-like helicase family, we broadened our scope and examined whether high processivity is also a feature of other UPF1-like helicases. To this end, we selected the human IGHMPB2 protein, a helicase linked to DSMA1 respiratory disease 12 , 13 . Guenther et al 35 previously described the ATP-dependent 5′–3′ helicase activity of a recombinant full-length IGHMPB2 on small RNA and DNA duplexes.…”

“…Future investigations will be necessary to determine the precise site of action of UPF1 during NMD and whether NMD partners modulate its residence time and its processivity. Exploration of the biophysical attributes of closely related UPF1-like helicases will be necessary to better understand their action in vivo and the consequences of their mutations linked to several human disorders 13 , 14 , 53 .…”

“…This family is formed of a group of 11 enzymes belonging to the SF1-B 5′–3′ helicases 10 . Among them one finds IGHMBP2 (immunoglobulin helicase mu-binding protein 2), a helicase related to mRNA translation and responsible for distal spinal muscular atrophy with respiratory distress type 1 12 , 13 , SetX/Sen1 (Senataxin), which is involved in transcription termination, R-loop resolving and is linked to amyotrophic lateral sclerosis 14 , and MOV10 (Moloney leukemia virus 10), which is involved in miRNA-dependent regulation 15 , 16 .…”

Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice‐site and Charcot‐Marie‐Tooth phenotype with early onset symptoms

“…The other is CMT2S [OMIM 616155] which has a milder presentation with distal muscle atrophy, weakness with areflexia and relatively minor sensory involvement (Khan et al., ; Lim, Bowler, Lai, & Song, ; Liu et al., ; Noensie & Dietz, ). Poor genotype‐phenotype correlation has been reported between these clinical variants (Pedurupillay et al., ).…”

Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

“…In affected infants, intrauterine growth retardation, weak cry, and suck or congenital foot deformities are the first symptoms followed by respiratory failure due to diaphragmatic paralysis (Figure 2(d)) and progressive muscle weakness. However, high variability in presentations within a family and a late onset and slow progressive form has been reported [66, 67]. Further peripheral neuropathy with no respiratory involvement has been described [68, 69].…”