Truncating and Missense Mutations in IGHMBP2 Cause Charcot-Marie Tooth Disease Type 2

Abstract

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.

Recessive hereditary motor and sensory neuropathy caused by IGHMBP2 gene mutation

“…Our results support the findings of Cottenie et al 7 and demonstrate 2 additional mutations in the IGHMBP2 gene associated with HMSN rather than SMARD1. Our findings suggest that genetic screening for IGHMBP2 mutations should be considered in patients with recessive HMSN.…”

“…5,6 However, a recent study revealed that truncating and missense mutations in IGHMBP2 could also lead to CMT. 7 Our proband presented with progressive weakness and sensory loss in distal limbs without any history of respiratory distress. As sensory neuropathy and history of respiratory distress are useful discriminating factors between HMSN and SMARD1, the clinical findings of this pedigree supported the diagnosis of HMSN rather than SMARD1.…”

A Rare Case of Charcot-Mari-Tooth Disease Type 2S in a 20-year-old Man

“…(7) However, in 2014, cases of patients from England, America, Serbia, Poland, Italy, Korea, and Vietnam were first described with a mutation in the same gene leading to the clinical presentation of HSMN2S (OMIM: 616155). (8) The young man turned to the doctor with complaints of a breathing disorder, which is typical for the clinical picture of spinal muscular atrophy with diaphragm paralysis. However, the conducted examinations showed no significant deviations from the norm.…”

Autosomal recessive axonal polyneuropathy in a sibling pair due to a novel homozygous mutation in IGHMBP2

“…Mutations in over 60 genes are known to be responsible for either the demyelinating or axonal subtypes of CMT; however, in spite of this number, a molecular diagnosis cannot be reached in approximately 75% of all axonal cases [14]. Mutations in IGHMBP2 had been exclusively associated with SMARD1 until a recent report by Cottenie et al [6] that identified patients with clinical features of CMT (sensorimotor axonal D.A. Dyment and H.J.…”

“…Mutations in this gene result in the degeneration of anterior horn cell alpha-motor neurons [4]. There is a spectrum of clinical presentations associated with mutations in IGHMBP2 [5][6][7][8][9][10][11], with individuals presenting with spinal muscular atrophy with respiratory distress (SMARD1; MIM# 604320) or Charcot-Marie-Tooth (CMT; MIM#616155) disease. SMARD1 is a rare autosomal recessive disorder that typically presents within the first two months of life and is characterized by respiratory failure, caused by diaphragmatic paralysis, and a severe infantile axonal neuropathy [5].…”