Novel SLC9A6 Variation in Female Carriers With Intellectual Disability and Atypical Parkinsonism

Haitian Nan; Yeon-Jeong Kim; Mai Tsuchiya; Aki Ishida; Hirotaka Haro; Masaki Hiraide; Toshihisa Ohtsuka; Yoshihisa Takiyama

doi:10.1212/NXG.0000000000000651

Novel SLC9A6 Variation in Female Carriers With Intellectual Disability and Atypical Parkinsonism

Neurol Genet. 2022 Jan 14;8(1):e651. doi: 10.1212/NXG.0000000000000651. eCollection 2022 Feb.

Authors

Haitian Nan¹, Yeon-Jeong Kim¹, Mai Tsuchiya¹, Aki Ishida¹, Hirotaka Haro¹, Masaki Hiraide¹, Toshihisa Ohtsuka¹, Yoshihisa Takiyama¹

Affiliation

¹ Department of Neurology (H.N., M.T., Y.T.), University of Yamanashi; Department of Biochemistry (Y.-J.K., T.O.), Graduate School of Medical Sciences, University of Yamanashi; Department of Rehabilitation (A.I.), Yamanashi University Hospital; Department of Orthopaedic Surgery (H.H.), University of Yamanashi; and Department of Neurology (M.H.), Kyonan Hospital, Yamanashi, Japan.

Abstract

Background and objectives: Variations in SLC9A6 cause the X-linked neurologic disorder Christianson syndrome in males. Meanwhile, female carriers with SLC9A6 variations may remain asymptomatic or develop intellectual disability, behavioral problems, and psychiatric illnesses. Only a few female carriers have been reported to have associated atypical parkinsonism in late life.

Methods: We present a Japanese family with a novel SLC9A6 variation identified by quad whole-exome sequencing analysis and a reverse phenotyping strategy. The molecular and cellular impacts of the W89R variation in vitro were examined.

Results: The missense variation (c.265T>C, p.Trp89Arg) in SLC9A6 cosegregated with atypical parkinsonism and intellectual disability in female carriers of this family. The female carriers in this family presented with bradykinesia, rigidity, and tremor, predominately on the right side. We found that the W89R variation changed membrane traffic of NHE6-harboring vesicles, indicating potential involvement in the disease pathogenesis.

Discussion: This study might have revealed an example of a monogenic origin of atypical parkinsonism in females with SLC9A6 variations and draw attention to this understudied female-specific phenotype in clinical practice.