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Molecular genetic analysis in 21 Chinese families with congenital insensitivity to pain with or without anhidrosis
Author(s) -
Zhao F.,
Mao B.,
Geng X.,
Ren X.,
Wang Y.,
Guan Y.,
Li S.,
Li L.,
Zhang S.,
You Y.,
Cao Y.,
Yang T.,
Zhao X.
Publication year - 2020
Publication title -
european journal of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 124
eISSN - 1468-1331
pISSN - 1351-5101
DOI - 10.1111/ene.14234
Subject(s) - missense mutation , medicine , tropomyosin receptor kinase a , genetics , anhidrosis , allele , receptor , mutation , gene , biology , neurotrophin , dermatology
Background and purpose Hereditary sensory and autonomic neuropathies (HSANs) are a group of clinically and genetically heterogeneous neurological disorders characterized by sensory dysfunctions. Here, 21 affected Chinese families are reported, including 19 with congenital insensitivity to pain with anhidrosis (CIPA; namely HSAN IV) and two with congenital insensitivity to pain (CIP; namely HSAN IID) caused by biallelic variations in NTRK1 and SCN9A , respectively, aiming to identify causative variants in these families and compare how different variants in NTRK1 affect the function of tropomyosin receptor kinase A (TrkA). Methods Recombinant plasmids harboring the wild‐type and six mutant alleles (p.Gln216*, p.Glu584Lys, p.Leu595Arg, p.Pro684Leu, p.Val709Leu and p.Arg765Cys) of NTRK1 cDNA were constructed and transfected into HEK293 cells. Results The results suggested that the five missense variants only presented a subtle influence on the expression level and glycosylation of TrkA but compromised the receptor phosphorylation. Our findings also suggested that a synonymous variant c.219C>T in NTRK1 may cause aberrant splicing, indicating a potential novel pathogenic mechanism of CIPA. Furthermore, gross deletion of SCN9A was first associated with CIP. Conclusions This study identified multiple forms of variants responsible for CIPA/CIP in the Chinese population and might provide new insights into the pathogenesis of CIPA.