Role of NF2 haploinsufficiency in NF2-associated polyneuropathy

Neurofibromatosis 2 (NF2) is a hereditary tumor disease characterized by bilateral vestibular schwannomas. Polyneuropathy seems to occur quite frequently in NF2 and in most cases, the etiology of this neuropathy is unclear, especially when the neuropathy is symmetric. NF2 is believed to follow the two-hit hypothesis. According to this, one allele is mutated in the germline, and the second hit is somatic and results in tumor formation. The second hit most frequently is a loss of the NF2 locus, often the entire chromosome 22. We set out to investigate the underlying genetics in peripheral nerve of NF2 patients with polyneuropathy. We identified NF2 patients with polyneuropathy in which we could detect the germline mutation and analyzed NF2 gene dosage in archived nerve biopsies from these patients using a newly developed method. We observed merlin haploinsufficiency in peripheral nerves of two different patients with NF2-related polyneuropathy. This finding was further supported by showing that approximately 50% merlin expression in a cell line using shRNA results in altered gene expression as previously shown in schwannomas. Thus, we suggest that reduced merlin gene dosage is relevant in NF2-associated polyneuropathy.