Biallelic FRA10AC1 variants cause a neurodevelopmental disorder with growth retardation

Abstract

The major spliceosome mediates pre-mRNA splicing by recognizing the highly conserved sequences at the 5’ and 3’ splice sites and the branch point. More than 150 proteins participate in the splicing process and are organized in the spliceosomal A, B, and C complexes. FRA10AC1 is a peripheral protein of the spliceosomal C complex and its ortholog in the green alga facilitates recognition or interaction with splice sites. We identified biallelic pathogenic variants in FRA10AC1 in five individuals from three consanguineous families. The two unrelated patients 1 and 2 with loss-of-function variants showed developmental delay, intellectual disability, and no speech, while three siblings with the c.494_496delAAG (p.Glu165del) variant had borderline to mild intellectual disability. All patients had microcephaly, hypoplasia or agenesis of the corpus callosum, growth retardation, and craniofacial dysmorphism. FRA10AC1 transcripts and proteins were drastically reduced or absent in fibroblasts of patients 1 and 2. In a heterologous expression system, the p. Glu165del variant impacts intrinsic stability of FRA10AC1 but does not affect its nuclear localization. By co-immunoprecipitation, we found ectopically expressed HA-FRA10AC1 in complex with endogenous DGCR14, another component of the spliceosomal C complex, while the splice factors CHERP, NKAP, RED, and SF3B2 could not be co-immunoprecipitated. Using an in vitro splicing reporter assay, we did not obtain evidence for FRA10AC1 deficiency to suppress missplicing events caused by mutations in the highly conserved dinucleotides of 5’ and 3’ splice sites in an in vitro splicing assay in patient-derived fibroblasts. Our data highlight the importance of specific peripheral spliceosomal C complex proteins for neurodevelopment. It remains possible that FRA10AC1 may have other and/or additional cellular functions, such as coupling of transcription and splicing reactions.

A Biallelic Variant in FRA10AC1 Is Associated With Neurodevelopmental Disorder and Growth Retardation

“…In conclusion, our study provides an independent corroboration of the recently reported autosomal recessive FRA10AC1 -associated syndromic neurodevelopmental disease and growth retardation. 1 This syndrome is characterized by failure to thrive, microcephaly, global developmental delay, generalized hypotonia, feeding problems, agenesis of corpus callosum, and dysmorphic features with or without congenital heart disease.…”

“…Recently reported cases presented with phenotypes similar to those in our patients. 1 They all had failure to thrive, microcephaly, global developmental delay, generalized hypotonia, feeding problems, brain anomalies (abnormal corpus callosum), and dysmorphic features with or without congenital heart disease ( Table ).…”

“…A recent study confirmed the association of biallelic inactivation of the spliceosomal C complex gene, FRA10AC1 , with a syndromic neurodevelopmental disease and growth retardation in 5 patients from 3 consanguineous families. 1 The reported variants have an overall loss of function (LOF) effect following an autosomal recessive mode of inheritance. In this study, we report a consanguineous family with 2 affected children with a similar phenotype.…”

Identification of N6-Methyladenosine-Related Gene Based Prognostic Signature to Predict Survival and Potential Therapeutic Drugs in Glioma

“…The gene participates in causing the folate-sensitive fragile site via a tandem CGG repeat region, but for years little is known about its biological function. A recent study has just revealed that biallelic pathogenic variants FRA10AC1 might lead to delay in neurodevelopment but no de nite cellular function can be clari ed [25] . GPR85 is a brainspeci c G protein-coupled receptor with a conserved identical sequence discovered in both humans and mice [26] .…”

Reconstruction of a Comprehensive Interactome and Experimental Data Analysis of FRA10AC1 May Provide Insights into Its Biological Role in Health and Disease

“…This indicates the possible role of FRA10AC1 in facilitating the recognition of or interaction between the acceptor and/or donor splice site and the branch point [ 19 ]. Interestingly, reminiscent of the clinical phenotypes caused by mutants of FMRP [ 12 , 13 ], clinical phenotypes have been reported that are caused by the biallelic loss of function variants of FRA10AC1 , which is characterized by strong intellectual disability and developmental delay [ 25 , 26 , 27 ]. Furthermore, in the context of a genome-wide association study (GWAS) aiming to identify genetic variants associated with amyloid-β 1–42 peptide levels in cerebrospinal fluid other than APOE ε4, as important biomarkers for Alzheimer’s disease, two FRA10AC1 SNPs—one intronic (a cis-eQTL) and one located less than 1kb upstream of the CGG repeat—were the top hits [ 28 ].…”