This report describes a newly identified association between the human gene UPF1 and cases of syndromic intellectual disability; the two cases characterized thus far are associated with de novo heterozygous variants. UPF1 encodes a component of a complex required for mRNA nuclear export, mRNA surveillance, and initiation of nonsense-mediated mRNA decay. There is a single orthologous gene in Drosophila, Dmel\Upf1, for which multiple genetic reagents have been generated including loss-of-function mutations, RNAi-targeting constructs, and mutations analogous to human disease-implicated variants. See the 'Disease-Implicated Variants' table below.
UAS constructs of the wild-type human Hsap\UPF1 gene have been introduced into flies, but have not been characterized in context of this disease model.
Animals homozygous for Dmel\Upf1 loss-of-function mutations typically die during the second larval stage. In a wild-type background, pan-neuronal overexpression of wild-type Upf1 results in some pupal lethality, with a subset of animals surviving to adulthood. In contrast, pan-neuronal overexpression of Dmel\Upf1 carrying a mutation analogous to either of the human disease-implicated variants causes lethality at earlier (embryonic or larval) stages, suggesting that both variants are functionally deleterious.
[updated Mar. 2025 by FlyBase; FBrf0222196]
Intellectual disability is characterized by impairments in intellectual functioning and adaptive behavior; symptoms must be present before a child becomes 18 years old (http://medical-dictionary.thefreedictionary.com/mental+retardation; 2016.01.19).
Intellectual disability can be subdivided into syndromic forms, characterized by cognitive impairment accompanied by dysmorphic features, malformations or neurological abnormalities, and nonsyndromic forms, characterized by cognitive impairment without additional features (Basel-Vanagaite, 2008; DOI: 10.1002/9780470015902.a0021454).
The two patients described thus far exhibit intellectual disability, psychomotor delay, speech delay, and mild dysmorphic facial features (Nakato et al; pubmed:39571789; FBrf0261302).
The 2 cases characterized thus far were shown to have de novo heterozygous variants in UPF1 (Nakato et al; pubmed:39571789; FBrf0261302).
UPF1 encodes an RNA-dependent helicase that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance; mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD).
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human UPF1 (1 Drosophila to 1 human).
