Molecular genetic analysis in 21 Chinese families with congenital insensitivity to pain with or without anhidrosis

BACKGROUND AND PURPOSE: Hereditary sensory and autonomic neuropathies (HSANs) are a group of clinically and genetically heterogeneous neurological disorders characterized by sensory dysfunctions. Here we report 21 affected Chinese families, including nineteen with congenital insensitivity to pain with anhidrosis (CIPA; namely HSAN IV) and two with congenital insensitivity to pain (CIP; namely HSAN IID), respectively caused by biallelic variations in NTRK1 and SCN9A, 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 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, we first associated gross deletion of SCN9A with CIP. CONCLUSIONS: This study identified multiple forms of variants responsible for CIPA/CIP in Chinese population and might provide new insights into pathogenesis of CIPA.