Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4 : A poly-glycine disease
(2024) In American Journal of Human Genetics 111(1). p.82-95- Abstract
Autosomal-dominant ataxia with sensory and autonomic neuropathy is a highly specific combined phenotype that we described in two Swedish kindreds in 2014; its genetic cause had remained unknown. Here, we report the discovery of exonic GGC trinucleotide repeat expansions, encoding poly-glycine, in zinc finger homeobox 3 (ZFHX3) in these families. The expansions were identified in whole-genome datasets within genomic segments that all affected family members shared. Non-expanded alleles carried one or more interruptions within the repeat. We also found ZFHX3 repeat expansions in three additional families, all from the region of Skåne in southern Sweden. Individuals with expanded repeats developed balance and gait disturbances at 15 to 60... (More)
Autosomal-dominant ataxia with sensory and autonomic neuropathy is a highly specific combined phenotype that we described in two Swedish kindreds in 2014; its genetic cause had remained unknown. Here, we report the discovery of exonic GGC trinucleotide repeat expansions, encoding poly-glycine, in zinc finger homeobox 3 (ZFHX3) in these families. The expansions were identified in whole-genome datasets within genomic segments that all affected family members shared. Non-expanded alleles carried one or more interruptions within the repeat. We also found ZFHX3 repeat expansions in three additional families, all from the region of Skåne in southern Sweden. Individuals with expanded repeats developed balance and gait disturbances at 15 to 60 years of age and had sensory neuropathy and slow saccades. Anticipation was observed in all families and correlated with different repeat lengths determined through long-read sequencing in two family members. The most severely affected individuals had marked autonomic dysfunction, with severe orthostatism as the most disabling clinical feature. Neuropathology revealed p62-positive intracytoplasmic and intranuclear inclusions in neurons of the central and enteric nervous system, as well as alpha-synuclein positivity. ZFHX3 is located within the 16q22 locus, to which spinocerebellar ataxia type 4 (SCA4) repeatedly had been mapped; the clinical phenotype in our families corresponded well with the unique phenotype described in SCA4, and the original SCA4 kindred originated from Sweden. ZFHX3 has known functions in neuronal development and differentiation n both the central and peripheral nervous system. Our findings demonstrate that SCA4 is caused by repeat expansions in ZFHX3.
(Less)
- author
- organization
-
- Clinical Neurogenetics (research group)
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- Genetic and epigenetic studies of pediatric leukemia (research group)
- Paediatrics (Lund)
- Clinical Sciences, Helsingborg
- Neurology, Lund
- Division of Clinical Genetics
- SciLifeLab Site@Lund (research group)
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- published
- subject
- in
- American Journal of Human Genetics
- volume
- 111
- issue
- 1
- pages
- 82 - 95
- publisher
- Cell Press
- external identifiers
-
- pmid:38035881
- scopus:85180324233
- ISSN
- 0002-9297
- DOI
- 10.1016/j.ajhg.2023.11.008
- project
- Investigating genetic causes of neurological movement disorders
- language
- English
- LU publication?
- yes
- additional info
- Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
- id
- 5f5837a7-45fc-43f9-ab14-4b8c533cc466
- date added to LUP
- 2023-12-05 21:49:28
- date last changed
- 2025-02-14 13:40:45
@article{5f5837a7-45fc-43f9-ab14-4b8c533cc466, abstract = {{<p>Autosomal-dominant ataxia with sensory and autonomic neuropathy is a highly specific combined phenotype that we described in two Swedish kindreds in 2014; its genetic cause had remained unknown. Here, we report the discovery of exonic GGC trinucleotide repeat expansions, encoding poly-glycine, in zinc finger homeobox 3 (ZFHX3) in these families. The expansions were identified in whole-genome datasets within genomic segments that all affected family members shared. Non-expanded alleles carried one or more interruptions within the repeat. We also found ZFHX3 repeat expansions in three additional families, all from the region of Skåne in southern Sweden. Individuals with expanded repeats developed balance and gait disturbances at 15 to 60 years of age and had sensory neuropathy and slow saccades. Anticipation was observed in all families and correlated with different repeat lengths determined through long-read sequencing in two family members. The most severely affected individuals had marked autonomic dysfunction, with severe orthostatism as the most disabling clinical feature. Neuropathology revealed p62-positive intracytoplasmic and intranuclear inclusions in neurons of the central and enteric nervous system, as well as alpha-synuclein positivity. ZFHX3 is located within the 16q22 locus, to which spinocerebellar ataxia type 4 (SCA4) repeatedly had been mapped; the clinical phenotype in our families corresponded well with the unique phenotype described in SCA4, and the original SCA4 kindred originated from Sweden. ZFHX3 has known functions in neuronal development and differentiation n both the central and peripheral nervous system. Our findings demonstrate that SCA4 is caused by repeat expansions in ZFHX3.</p>}}, author = {{Wallenius, Joel and Kafantari, Efthymia and Jhaveri, Emma and Gorcenco, Sorina and Ameur, Adam and Karremo, Christin and Dobloug, Sigurd and Karrman, Kristina and de Koning, Tom and Ilinca, Andreea and Landqvist Waldö, Maria and Arvidsson, Andreas and Persson, Staffan and Englund, Elisabet and Ehrencrona, Hans and Puschmann, Andreas}}, issn = {{0002-9297}}, language = {{eng}}, number = {{1}}, pages = {{82--95}}, publisher = {{Cell Press}}, series = {{American Journal of Human Genetics}}, title = {{Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4 : A poly-glycine disease}}, url = {{http://dx.doi.org/10.1016/j.ajhg.2023.11.008}}, doi = {{10.1016/j.ajhg.2023.11.008}}, volume = {{111}}, year = {{2024}}, }