Abstract
In 2008, we reported a clinically and genetically new type of autosomal dominant disorder of motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough. To identify the nucleotide variant causative of this disease, we reanalyzed the linkage of the original Japanese pedigree including seven newly ascertained subjects with updated information. We assigned the locus of the disease to 1p13.3-q23 (maximum logarithm-of-odds score = 2.71). Exome sequencing for five patients and one healthy relative from the pedigree revealed 2526 patient-specific single-nucleotide variants (SNVs). By rigorous filtering processes using public databases, our linkage results, and functional prediction, followed by Sanger sequencing of the pedigree and 520 healthy Japanese individuals, we identified an intronic SNV in IQGAP3, a gene known to be associated with neurite outgrowth. Upon pathological examination of the sural nerve, moderate, chronic, mainly axonal neuropathy was observed. By histochemical analyses, we observed a patient-specific increase of IQGAP3 expression in the sural nerve. We concluded that the variant of IQGAP3 is associated with the disease in our pedigree.
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Data availability
The IQGAP3 variant and the FLG variant data have been deposited to and openly available from ClinVar (Submission IDs: SUB6424734, IQGAP3; https://www.ncbi.nlm.nih.gov/clinvar/variation/694497/, FLG; https://www.ncbi.nlm.nih.gov/clinvar/variation/694498/). The data sets of this study are available from the corresponding author on reasonable request.
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Acknowledgements
We thank patients and their family members for participation in the study. The authors would like to thank Enago (www.enago.jp) for the English language review.
Funding
This work was supported by the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University, and by JSPS KAKENHI (Grant number: 26460411 to S Miura).
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S Miura and H Shibata contributed to the study concept and design and analysis. S Miura, KK, TS, EM, KN, RF, S Mori, FU, TI, KY contributed to acquisition of data. S Mori, TI, H Saitsu contributed to the interpretation of the data. S Miura and H Shibata are responsible for the overall content.
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Miura, S., Kosaka, K., Shimojo, T. et al. Intronic variant in IQGAP3 associated with hereditary neuropathy with proximal lower dominancy, urinary disturbance, and paroxysmal dry cough. J Hum Genet 65, 717–725 (2020). https://doi.org/10.1038/s10038-020-0761-7
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DOI: https://doi.org/10.1038/s10038-020-0761-7