TY - JOUR
T1 - Rare Variants in MME, Encoding Metalloprotease Neprilysin, Are Linked to Late-Onset Autosomal-Dominant Axonal Polyneuropathies
AU - Auer-Grumbach, Michaela
AU - Toegel, Stefan
AU - Schabhüttl, Maria
AU - Weinmann, Daniela
AU - Chiari, Catharina
AU - Bennett, David L L.H.
AU - Beetz, Christian
AU - Klein, Dennis
AU - Andersen, Peter M M.
AU - Böhme, Ilka
AU - Fink-Puches, Regina
AU - Gonzalez, Michael
AU - Harms, Matthew B B.
AU - Motley, William
AU - Reilly, Mary M M.
AU - Renner, Wilfried
AU - Rudnik-Schöneborn, Sabine
AU - Schlotter-Weigel, Beate
AU - Themistocleous, Andreas C C.
AU - Weishaupt, Jochen H H.
AU - Ludolph, Albert C C.
AU - Wieland, Thomas
AU - Tao, Feifei
AU - Abreu, Lisa
AU - Windhager, Reinhard
AU - Zitzelsberger, Manuela
AU - Strom, Tim M M.
AU - Walther, Thomas
AU - Scherer, Steven S S.
AU - Züchner, Stephan
AU - Martini, Rudolf
AU - Senderek, Jan
N1 - Funding Information:
We are grateful to families and study individuals for their contribution. This work was supported by the Austrian Science Fund (FWF, P27634FW to M.A.-G.), the Friedrich-Baur-Stiftung and the Fritz-Thyssen-Stiftung (to J.S.), NIH (U54NS065712 to S.Z. and S.S.S. and R01NS075764 to S.Z.), the Judy Seltzer Levenson Memorial Fund for CMT Research (to S.S.S.), the CMT Association, and ?The Genesis Project.? We also thank the Inherited Neuropathy Consortium for advice and general support. S.R.-S., B.S.-W., D.K., R.M., and J.S. are members of the German network on Charcot-Marie-Tooth neuropathies (CMT-NET) funded by the German Federal Ministry of Education and Research (BMBF).
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2016.07.008
DO - 10.1016/j.ajhg.2016.07.008
M3 - Article
C2 - 27588448
AN - SCOPUS:85015505768
VL - 99
SP - 607
EP - 623
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -