Objective: To report a novel mutation not been previously reported in large, multi-ethnic general populations, in the protein kinase C gamma (PRKCG) gene causing spinocerebellar ataxia 14 (SCA14) in a large family with several affected family members with ataxia.

Background: SCA14 is a rare mild autosomal dominant cerebellar ataxia characterized by slowly progressive ataxia, dysarthria and nystagmus with degeneration of the cerebellum.  SCA14 is caused by missense mutations in the PRKCG gene (19q13.4) encoding protein kinase C gamma.

Method: Our patients come from a large family of 15 siblings, with 7 affected and 8 unaffected with ataxia.  The first patient seen was a 72 year old woman with a slowly progressive ataxia for 30 years.  Her gait and balance had progressively worsened over time, and the visit was prompted by the need to begin using a walker due to frequent falls. Her neurological exam revealed cerebellar dysarthria, impaired rapid alternating and heel to shin movements, and a wide-based, short steppage gait.  MRI brain revealed global cerebellar volume loss moderate in severity.  She also had cognitive deficits, mainly memory loss and attention deficits.  One unaffected female sibling was also evaluated.  Their 74 year old affected brother was subsequently evaluated and he reported issues with his balance, gait, and speech.  He was falling once per day despite using a walking stick.  His exam revealed nystagmus, impaired rapid alternating and heel to shin movements, dysmetria, and a wide-based, short-steppage gait similar to that of his sister.  MRI brain showed generalized cerebellar atrophy.  Finally, this patient’s 40 year old affected daughter was also evaluated.

Results: The affected family members underwent sequential genetic testing which revealed that they all carried a heterozygous missense mutation in the PRKCG gene (c.68G>A; p.Gly23Glu).  Both sorting intolerant from tolerant (SIFT) and polymorphism phenotyping (PolyPhen)-2.2.2 predicted that this variant is pathogenic for SCA14 as it is found in an important functional domain/region of the protein.

Conclusion: A SCA-14-linked family with a novel heterozygous missense mutation in the PRKCG gene was identified and diagnosis confirmed after over 30 years of symptoms.  This demonstrated the utility of exome sequencing to screen heterogeneous genetic disorders such as ataxia which may result in detection of novel mutations.

References: Asai, H., Hirano, M., Shimada, K., Kiriyama, T., Furiya, Y., Ikeda, M., Iwamoto, T., Mori, T., Nishinaka, K., Konishi, N., Udaka, F., Ueno, S. Protein kinase C-gamma, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin. Hum. Molec. Genet. 18: 3533-3543, 2009. Chen, D.-H., Brkanac, Z., Verlinde, C. L. M. J., Tan, X.-J., Bylenok, L., Nochlin, D., Matsushita, M., Lipe, H., Wolff, J., Fernandez, M., Cimino, P. J., Bird, T. D., Raskind, W. H. Missense mutations in the regulatory domain of PKC-gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am. J. Hum. Genet. 72: 839-849, 2003. Klebe, S., Durr, A., Rentschler, A., Hahn-Barma, V., Abele, M., Bouslam, N., Schols, L., Jedynak, P., Forlani, S., Denis, E., Dussert, C., Agid, Y., Bauer, P., Globas, C., Wullner, U., Brice, A., Riess, O., Stevanin, G. New mutations in protein kinase C gamma associated with spinocerebellar ataxia type 14. Ann. Neurol. 58: 720-729, 2005. Stevanin, G., Hahn, V., Lohmann, E., Bouslam, N., Gouttard, M., Soumphonphakdy, C., Welter, M.-L., Ollagnon-Roman, E., Lemainque, A., Ruberg, M., Brice, A., Durr, A. Mutation in the catalytic domain of protein kinase C gamma and extension of the phenotype associated with spinocerebellar ataxia type 14. Arch. Neurol. 61: 1242-1248, 2004. Yabe, I., Sasaki, H., Chen, D.-H., Raskind, W. H., Bird, T. D., Yamashita, I., Tsuji, S., Kikuchi, S., Tashiro, K. Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma. Arch. Neurol. 60: 1749-1751, 2003.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-mutation-in-the-protein-kinase-c-gamma-gene-causing-spinocerebellar-ataxia-14-in-a-large-family/