Journal Article

DZNE-2020-00371

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Severe white matter damage in SHANK3 deficiency: a human and translational study.

Jesse, S. (Corresponding author) ; Müller, H.-P. ; Schoen, M. ; Asoglu, H. ; Bockmann, J. ; Huppertz, H.-J. ; Rasche, V. ; Ludolph, A.DZNE* ; Böckers, T.DZNE* ; Kassubek, J.

2020
Wiley Chichester [u.a.]

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Please use a persistent id in citations: doi:10.1002/acn3.50959

Abstract: Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan-McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of SHANK3 models have contributed to the understanding of how the loss of the synaptic protein SHANK3 affects neuronal function.Diffusion tensor imaging-based and automatic volumetric brain mapping were performed in 12 SHANK3-deficient participants (mean age 19 ± 15 years) versus 14 age- and gender-matched controls (mean age 29 ± 5 years). Using whole brain-based spatial statistics, we observed a highly significant pattern of white matter alterations in participants with SHANK3 mutations with focus on the long association fiber tracts, particularly the uncinate tract and the inferior fronto-occipital fasciculus. In contrast, only subtle gray matter volumetric abnormalities were detectable. In a back-translational approach, we observed similar white matter alterations in heterozygous isoform-specific Shank3 knockout (KO) mice. Here, in the baseline data sets, the comparison of Shank3 heterozygous KO vs wildtype showed significant fractional anisotropy reduction of the long fiber tract systems in the KO model. The multiparametric Magnetic Resonance Imaging (MRI) analysis by DTI and volumetry demonstrated a pathology pattern with severe white matter alterations and only subtle gray matter changes in the animal model.In summary, these translational data provide strong evidence that the SHANK3-deficiency-associated pathomechanism presents predominantly with a white matter disease. Further studies should concentrate on the role of SHANK3 during early axonal pathfinding/wiring and in myelin formation.

Keyword(s): Adolescent (MeSH) ; Adult (MeSH) ; Animals (MeSH) ; Autism Spectrum Disorder: diagnostic imaging (MeSH) ; Autism Spectrum Disorder: genetics (MeSH) ; Autism Spectrum Disorder: pathology (MeSH) ; Autism Spectrum Disorder: physiopathology (MeSH) ; Child (MeSH) ; Child, Preschool (MeSH) ; Chromosome Deletion (MeSH) ; Chromosome Disorders: diagnostic imaging (MeSH) ; Chromosome Disorders: genetics (MeSH) ; Chromosome Disorders: pathology (MeSH) ; Chromosome Disorders: physiopathology (MeSH) ; Chromosomes, Human, Pair 22: genetics (MeSH) ; Diffusion Tensor Imaging (MeSH) ; Disease Models, Animal (MeSH) ; Female (MeSH) ; Gray Matter: diagnostic imaging (MeSH) ; Gray Matter: pathology (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Knockout (MeSH) ; Microfilament Proteins (MeSH) ; Middle Aged (MeSH) ; Nerve Tissue Proteins: deficiency (MeSH) ; Neurodevelopmental Disorders: diagnostic imaging (MeSH) ; Neurodevelopmental Disorders: genetics (MeSH) ; Neurodevelopmental Disorders: pathology (MeSH) ; Neurodevelopmental Disorders: physiopathology (MeSH) ; Translational Research, Biomedical (MeSH) ; White Matter: diagnostic imaging (MeSH) ; White Matter: pathology (MeSH) ; Young Adult (MeSH)

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Contributing Institute(s):

1. Clinical Study Center Ulm (Clinical Study Center Ulm)
2. Translational Protein Biochemistry (AG Böckers)

Research Program(s):

1. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)
2. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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Database coverage:
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