Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis.
Neurobiology of Aging. 2017-10-01; 58: 239.e11-239.e20
DOI: 10.1016/j.neurobiolaging.2017.06.018
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1. Neurobiol Aging. 2017 Oct;58:239.e11-239.e20. doi:
10.1016/j.neurobiolaging.2017.06.018. Epub 2017 Jun 24.
Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical
hereditary spastic paraplegia phenotype through defective HSP70-mediated
proteolysis.
Teyssou E(1), Chartier L(1), Amador MD(2), Lam R(1), Lautrette G(3), Nicol M(3),
Machat S(3), Da Barroca S(1), Moigneu C(1), Mairey M(4), Larmonier T(5), Saker
S(5), Dussert C(1), Forlani S(1), Fontaine B(6), Seilhean D(7), Bohl D(1),
Boillée S(1), Meininger V(8), Couratier P(3), Salachas F(6), Stevanin G(9),
Millecamps S(10).
Author information:
(1)Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127,
Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
(2)Département de Neurologie, Assistance Publique Hôpitaux de Paris (APHP),
Centre de ressources et de compétences SLA Ile de France, Hôpital de la
Pitié-Salpêtrière, Paris, France.
(3)Service de Neurologie, Centre de ressources et de compétences SLA, CHU
Dupuytren, Limoges, France.
(4)Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127,
Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Ecole Pratique
des Hautes Etudes, EPHE, Université de recherche Paris Sciences et Lettres,
Paris, France.
(5)Banque d’ADN et de cellules du Généthon, Evry, France.
(6)Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127,
Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Département de
Neurologie, Assistance Publique Hôpitaux de Paris (APHP), Centre de ressources et
de compétences SLA Ile de France, Hôpital de la Pitié-Salpêtrière, Paris, France.
(7)Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127,
Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Département de
Neuropathologie, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
(8)Département de Neurologie, Assistance Publique Hôpitaux de Paris (APHP),
Centre de ressources et de compétences SLA Ile de France, Hôpital de la
Pitié-Salpêtrière, Paris, France; Hôpital des Peupliers, Ramsay Générale de
Santé, Paris, France.
(9)Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127,
Institut du Cerveau et de la Moelle épinière, ICM, Paris, France; Ecole Pratique
des Hautes Etudes, EPHE, Université de recherche Paris Sciences et Lettres,
Paris, France; Centre de Référence de Neurogénétique, Fédération de Génétique,
APHP, Hôpital Pitié-Salpêtrière, Paris, France.
(10)Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 6 UMRS1127,
Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. Electronic
address: .
Mutations in UBQLN2 have been associated with rare cases of X-linked juvenile and
adult forms of amyotrophic lateral sclerosis (ALS) and ALS linked to
frontotemporal dementia (FTD). Here, we report 1 known (c.1489C>T, p.Pro497Ser,
P497S) and 3 novel (c.1481C>T, p.Pro494Leu, P494L; c.1498C>T, p.Pro500Ser, P500S;
and c.1516C>G, p.Pro506Ala, P506A) missense mutations in the PXX domain of UBQLN2
in familial motor neuron diseases including ALS and spastic paraplegia (SP). A
novel missense mutation (c.1462G>A, p.Ala488Thr, A488T) adjacent to this hotspot
UBQLN2 domain was identified in a sporadic case of ALS. These mutations are
conserved in mammals, are absent from ExAC and gnomAD browsers, and are predicted
to be deleterious by SIFT in silico analysis. Patient lymphoblasts carrying a
UBQLN2 mutation showed absence of ubiquilin-2 accumulation, disrupted binding
with HSP70, and impaired autophagic pathway. Our results confirm the role of PXX
repeat in ALS pathogenesis, show that UBQLN2-linked disease can manifest like a
SP phenotype, evidence a highly reduced disease penetrance in females carrying
UBQLN2 mutations, which is important information for genetic counseling, and
underline the pivotal role of ubiquilin-2 in proteolysis regulation pathways.
Copyright © 2017 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.neurobiolaging.2017.06.018
PMID: 28716533 [Indexed for MEDLINE]