Two Angelman families with unusually advanced neurodevelopment carry a start codon variant in the most highly expressed <i>UBE3A</i> isoform

Sadhwani, Anjali; Sanjana, Neville E.; Willen, Jennifer M.; Calculator, Stephen N.; Black, Emily; Bean, Lora Jh; Li, Hong; Tan, Wen‐Hann

doi:10.1002/ajmg.a.38831

Cited by 20 publications

(18 citation statements)

References 24 publications

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“…A study in which specifically the cytosolic mUBE3A-Iso2 was deleted in mice, showed no behavioral phenotypes and changes in synaptic function, and the behavioral deficits of AS mice could be fully recapitulated by selective deletion of the nuclear mUBE3A-Iso3 isoform ( 9 ). Recently three individuals with AS have been described who specifically lack the nuclear hUBE3A-Iso1 ( 15 ). Based on the isoform localization, we determined in this study, we would predict that this mutation causes a loss of most of the nuclear UBE3A and that the cytosolic UBE3A levels remain the same.…”

Section: Discussionmentioning

confidence: 99%

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Conserved UBE3A subcellular distribution between human and mice is facilitated by non-homologous isoforms

Zampeta

Sonzogni

Niggl

et al. 2020

Human Molecular Genetics

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The human UBE3A gene, which is essential for normal neurodevelopment, encodes three Ubiquitin E3 ligase A (UBE3A) protein isoforms. However, the subcellular localization and relative abundance of these human UBE3A isoforms are unknown. We found, as previously reported in mice, that UBE3A is predominantly nuclear in human neurons. However, this conserved subcellular distribution is achieved by strikingly distinct cis-acting mechanisms. A single amino-acid deletion in the N-terminus of human hUBE3A-Iso3, which is homologous to cytosolic mouse mUBE3A-Iso2, results in its translocation to the nucleus. This mutation is shared with apes and Old-World monkeys and was preceded by the appearance of the cytosolic hUBE3A-Iso2 isoform. This isoform arose after the lineage of New World monkeys and Old World monkeys separated from the Tarsiers (Tarsiidae). Due to the loss of a single nucleotide in this non-coding exon, the exon became in frame with the remainder of the UBE3A protein. RNA-seq analysis of human brain samples showed that the human UBE3A isoforms arise by alternative splicing. Consistent with the predominant nuclear enrichment of UBE3A in human neurons, the two nuclear localized isoforms, hUBE3A-Iso1 and -Iso3, are the most abundantly expressed isoforms of UBE3A, while hUBE3A-Iso2 maintains a small pool of cytosolic UBE3A. Our findings provide new insight into UBE3A localization and evolution, and may have important implications for gene therapy approaches in Angelman Syndrome.

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Section: Discussionmentioning

confidence: 99%

“…In addition, a third human UBE3A isoform has been reported (hUBE3A-Iso2), which has no homologue in mice ( 14 ). Similar to mice, loss of the most abundantly expressed short isoform (hUBE3A-Iso1) in human results in a AS-like phenotype ( 15 ), but the localization of this human isoform has not been established.…”

Section: Introductionmentioning

confidence: 99%

Conserved UBE3A subcellular distribution between human and mice is facilitated by non-homologous isoforms

Zampeta

Sonzogni

Niggl

et al. 2020

Human Molecular Genetics

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“…One of UBE3A's salient molecular features is its shift from the cytoplasm to nucleus upon neuronal maturation Dindot et al, 2008;Gustin et al, 2010), likely driven by shifts in isoform expression (LaSalle et al, 2015;Miao et al, 2013;Sadhwani et al, 2018). Importantly, it was recently shown that mice lacking nuclear UBE3A show electrophysiological and behavioral deficits similar to other AS model mice that lack maternal UBE3A (Avagliano Trezza et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Human cerebral organoids capture the spatiotemporal complexity and disease dynamics of UBE3A

Sen

Voulgaropoulos

Drobná

et al. 2019

Preprint

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Human neurodevelopment and its associated diseases are complex and challenging to study. This has driven recent excitement for human cerebral organoids (hCOs) as research and screening tools. These models are steadily proving their utility; however, it remains unclear what limits they will face in recapitulating the complexities of neurodevelopment and disease.Here we show that their utility extends to key (epi)genetic and disease processes that are complex in space and time. Specifically, hCOs capture UBE3A's dynamically imprinted expression and subcellular localization patterns. Furthermore, given UBE3A's direct links to Angelman Syndrome and Autism Spectrum Disorder, we show that hCOs respond to candidate small molecule therapeutics. This work demonstrates that hCOs can provide important insights to focus the scope of mechanistic and therapeutic strategies including revealing difficult to access prenatal developmental time windows and cell types key to disease etiology.

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“…Interestingly, although start codon variants are often associated with a severe disease course, 10,11 there are several reports of disease causing start codon variants describing a milder phenotype. [12][13][14] The residual protein synthesis in case of such a start codon variant may be explained by the production of a shorter but still partly functional protein because of the use of an alternative downstream start codon, either in the mutated transcript itself or in alternatively spliced transcripts. The CLN3 protein is known to exist in multiple isoforms, of which a few have a putative later start position-recently extensively reviewed by Mirza et al 6and thus do not encompass the mutated c.1A > C base pair as present in our patients.…”

Section: Discussionmentioning

confidence: 99%

The c.1A > C start codon mutation in CLN3 is associated with a protracted disease course

et al. 2020

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Background CLN3 disease is a disorder of lysosomal homeostasis predominantly affecting the retina and the brain. The severity of the underlying mutations in CLN3 particularly determines onset and course of neurological deterioration. Given the highly conserved start codon code among eukaryotic species, we expected a variant in the start codon of CLN3 to give rise to the classical, that is, severe, phenotype. Case series We present three patients with an identical CLN3 genotype (compound heterozygosity for the common 1 kb deletion in combination with a c.1A > C start codon variant) who all displayed a more attenuated phenotype than expected. While their retinal phenotype was similar to as expected in classical CLN3 disease, their neurological phenotype was delayed. Two patients had an early onset of cognitive impairment, but a particularly slow deterioration afterwards without any obvious motor impairment. The third patient also had a late onset of cognitive impairment. Conclusions Contrasting our initial expectations, patients with a start codon variant in CLN3 may display a protracted phenotype. Future work will have to reveal the exact mechanism behind the assumed residual protein synthesis, and determine whether this may be eligible to start codon targeted therapy.

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Two Angelman families with unusually advanced neurodevelopment carry a start codon variant in the most highly expressed UBE3A isoform

Cited by 20 publications

References 24 publications

Conserved UBE3A subcellular distribution between human and mice is facilitated by non-homologous isoforms

Conserved UBE3A subcellular distribution between human and mice is facilitated by non-homologous isoforms

Human cerebral organoids capture the spatiotemporal complexity and disease dynamics of UBE3A

The c.1A > C start codon mutation in CLN3 is associated with a protracted disease course

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