Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies

Abstract

Axonal polyneuropathies are a frequent cause of progressive disability in the elderly. Common etiologies comprise diabetes mellitus, paraproteinaemia, and inflammatory disorders, but often the underlying causes remain elusive. Late-onset axonal Charcot-Marie-Tooth neuropathy (CMT2) is an autosomal-dominantly inherited condition that manifests in the second half of life and is genetically largely unexplained. We assumed age-dependent penetrance of mutations in a so far unknown gene causing late-onset CMT2. We screened 51 index case subjects with late-onset CMT2 for mutations by whole-exome (WES) and Sanger sequencing and subsequently queried WES repositories for further case subjects carrying mutations in the identified candidate gene. We studied nerve pathology and tissue levels and function of the abnormal protein in order to explore consequences of the mutations. Altogether, we observed heterozygous rare loss-of-function and missense mutations in MME encoding the metalloprotease neprilysin in 19 index case subjects diagnosed with axonal polyneuropathies or neurodegenerative conditions involving the peripheral nervous system. MME mutations segregated in an autosomal-dominant fashion with age-related incomplete penetrance and some affected individuals were isolated case subjects. We also found that MME mutations resulted in strongly decreased tissue availability of neprilysin and impaired enzymatic activity. Although neprilysin is known to degrade β-amyloid, we observed no increased amyloid deposition or increased incidence of dementia in individuals with MME mutations. Detection of MME mutations is expected to increase the diagnostic yield in late-onset polyneuropathies, and it will be tempting to explore whether substances that can elevate neprilysin activity could be a rational option for treatment.

Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

“…Conversely, three out of the 17 mutations detected in this study (p.Trp24*, p.Pro156Leufs*14 and p.Arg448*) were described previously in European and American patients, and linked to late-onset AD polyneuropathies 8. In our cohort, the healthy relatives carrying the heterozygous LoF mutations (such as, p.Pro156Leufs*14, p.Arg448* and p.Trp750Glyfs*24), who were older than the affected individuals, did not present any signs of neuropathy.…”

“…The Neprilysin (NEP) protein is expressed in many tissues,14 including the PNS and central nervous system (CNS),15 16 although NEP-deficient mice do not show any obvious abnormalities in motor performance or degeneration of their peripheral nerves 8. Neurodegeneration in a length-dependent neuropathy may not be so evident in a mouse model given their short life span and the reduced vulnerability of shorter axons.…”

“…Likewise, several cases of autosomal dominant (AD) late-onset neuropathies in European and American families were linked to MME variants 8. Here, we present data from a series of patients with CMT, distal hereditary motor neuropathy (dHMN) and familial amyotrophic lateral sclerosis (fALS) without genetic diagnosis, but who were studied using a panel of 119 genes causing neuropathy and/or ALS.…”

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants

“…The MME c.674G > C (p.G225A) missense variant was absent in our unaffected controls, but it is represented at low frequency in public control datasets (MAF = 0.02%); although the prevalence of primary headache in public datasets is unknown, this could reflect incomplete penetrance and the interaction with other genetic or environmental factors. Furthermore, rare loss-of-function and missense MME variants were recently associated to late onset dominant axonal polyneuropathies (Charcot-Marie-Tooth Neuropathy Type 2, CMT2; spinocerebellar ataxia with neuropathy, SCA43) [38, 39] and to a rare autosomal recessive variant of CMT2 [40]; none of the neuropathy patients described in these studies was reported to have migraine or CH symptoms, however individuals with MME mutations were reported to experience painful sensations [38]. Given the variety of NEP target peptides and their wide expression pattern, it is plausible that MME deleterious variants may contribute to the aetiology of different neurological conditions, and further studies are needed to identify the mechanisms underlying the phenotypic differences.…”

Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination

“…The effects of MTMR5 loss-of-function may be exacerbated in humans relative to mice, potentially explaining the greater reductions in myelinated axon numbers observed in patients (28,29). Although the precise cause of this feature is unclear, several mouse models of axonal CMT have shown phenotypes milder than their corresponding human conditions (36,(44)(45)(46)(47)(48). Incomplete radial sorting can be caused by defects in both axons and Schwann cells (1,49).…”