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Other entities represented in this entry:
HGNC Approved Gene Symbol: FRA10AC1
Cytogenetic location: 10q23.33 Genomic coordinates (GRCh38) : 10:93,667,883-93,702,959 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.33 | Neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities | 620113 | Autosomal recessive | 3 |
The FRA10AC1 gene encodes a component of the spliceosomal C complex that is required to process functional mRNA (summary by von Elsner et al., 2022).
Sarafidou et al. (2004) identified the FRA10AC1 gene within the rare FRA10A folate-sensitive fragile site on chromosome 10q23.3. The major FRA10AC1 transcript encodes a deduced 315-amino acid protein with a calculated molecular mass of 37.5 kD. FRA10AC1 contains several sites for serine phosphorylation and a bipartite nuclear localization signal embedded within a larger lysine-rich region. Northern blot analysis detected a 1.45-kb transcript in all adult tissues examined. Strongest expression was in brain, heart, skeletal muscle, kidney, and liver. All other tissues expressed low levels of FRA10AC1 except leukocytes, in which expression was barely detectable. RT-PCR confirmed that FRA10AC1 is ubiquitously expressed and detected splice variants in some tissues, particularly in ovary and testis. Sarafidou et al. (2004) identified 5 splice variants that differ in their C termini. Transiently transfected COS-7 cells expressed FRA10AC1 in the nucleoplasm. The FRA10AC1 protein is conserved between species. The human protein shares 86% identity with mouse Fra10ac1 and about 35% identity with plant and C. elegans Fra10ac1. A central sequence of FRA10AC1 is most highly conserved.
Sarafidou et al. (2004) determined that the FRA10AC1 gene contains 19 exons and spans about 33 kb. Exon 1 is untranslated, and the 5-prime UTR is part of a CpG island.
By FISH, Sarafidou et al. (2004) mapped the FRA10AC1 gene to chromosome 10q23.3, between the PDE6C (600827) and LGI1 (604619) genes. FRA10AC1 is transcribed from telomere to centromere.
Sarafidou et al. (2004) mapped the mouse Fra10ac1 gene to chromosome 19C2-C3 in a region that shows homology of synteny to human chromosome 10q23-q24.
Through in vitro coimmunoprecipitation studies, von Elsner et al. (2022) found that FRA10AC1 interacted with DGCR14 (ESS2; 601755), another component of the spliceosomal C complex.
Sarafidou et al. (2004) tested 81 individuals from 40 CEPH families and identified alleles with 8, 9, 10, or 14 CGG repeats within the 5-prime UTR of the FRA10AC1 gene. The most common allele contained 9 CGG repeats. In contrast, individuals cytogenetically expressing the FRA10A fragile site had at least 200 CGG repeats in the FRA10AC1 gene. All FRA10A carriers had 1 normal allele, and the expanded allele was hypermethylated and not transcribed. Sarafidou et al. (2004) concluded that, in the heterozygous state, FRA10A is likely a benign folate-sensitive fragile site.
De Leon-Luis et al. (2005) reported prenatal diagnosis of a maternally inherited FRA10A site and heterozygous 10q23 deletion in amniotic cells cultured in non-folic deprived medium. The child was born without any anomalies and was normal at age 25 months. None of the 4 heterozygous adult carriers of FRA10A had any congenital anomalies or medical disorders, suggesting it is a benign finding.
In 5 patients from 3 unrelated consanguineous Arabic families with neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities (NEDGFC; 620113), von Elsner et al. (2022) identified 3 different homozygous mutations in the FRA10AC1 gene (608866.0001-608866.0003). The patients were ascertained through the GeneMatcher program after genetic analysis identified the mutations. The mutations were absent from gnomAD and segregated with the disorder in each family. Patients from 2 families carried an intragenic deletion (608866.0001) and a frameshift mutation (608866.0002), respectively, and fibroblasts derived from these patients showed reduced FRA10AC1 transcript and protein levels compared to controls, suggesting that the mutations trigger nonsense-mediated mRNA decay and result in a loss of function. Three sibs in the third family carried an in-frame deletion of 1 residue (Glu165del; 608866.0003), which was demonstrated in vitro to cause a reduction of FRA10AC1 levels, although the mutant protein localized normally to the nucleus. These findings indicated a milder adverse impact of this mutation on protein function. The sibs in this family also had a less severe phenotype compared to the patients in the other 2 families, suggesting a possible genotype/phenotype correlation. An in vitro splicing reporter assay using patient fibroblasts (families 1 and 2) showed that FRA10AC1 deficiency did not suppress missplicing events caused by mutations in highly conserved splice sites. Transcriptome analysis of patient fibroblasts did not show a significant disturbance in alternative splicing integrity. Von Elsner et al. (2022) suggested that there may be a cell type-specific function of FRA10AC1, such that neurons may be more susceptible to splicing alterations, especially during development. In addition, FRA10AC1 may have additional cellular functions, such as coupling of transcription and splicing reactions.
In 3 patients from 2 unrelated consanguineous families with NEDGFC, Banka et al. (2022) identified homozygous loss-of-function mutations in the FRA10AC1 gene (608866.0004 and 608866.0005). RNA-seq analysis of fibroblasts derived from 1 patient showed a significant number of differentially expressed genes, including those that encode developmental transcription factors, compared to controls. However, there were not major changes in splicing. The study supported the conclusions reached by von Elsner et al. (2022).
In 2 sibs, born in a highly consanguineous Arab family, with NEDGFC, Alsaleh et al. (2022) identified a homozygous nonsense mutation in the FRA10AC1 gene (R161X; 607766.0006). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to trigger nonsense-mediated mRNA decay and result in loss of function.
Sutherland (1979) made the serendipitous observation that development of fragile sites was enhanced by medium deficient in folic acid; addition of folic acid or folinic acid inhibited fragile sites and the folic acid antagonist methotrexate enhanced them. Elevated pH enhanced the fragile sites on chromosomes 2q, 10q, and Xq28. Three classes of fragile sites may exist; the majority are sensitive to folic acid and thymidine, but the one at chromosome 16q22 is resistant, and the common one at chromosome 10q25 requires BrdU for expression (Sutherland et al., 1980). The locations of the fragile sites are chromosomes 2q11, 9q31, 10q23, 10q25, 11q13, 12q13, 16p12, 16q22, 20p11, and Xq28. All cells in a given culture do not show the fragile site. The morphologic change is heritable in a mendelian manner. The frequency of each autosomal fragile site is on the order of 1 or 2 per 4,000 persons, and the overall frequency of autosomal fragile sites is about 0.2%. Fragile sites may reflect gene amplification and activation as a result of nutritional deficiency in culture. Mouse cells that acquire resistance to methotrexate show a possibly identical change.
Sutherland (1982) studied the frequency of the 9 known folic acid-sensitive fragile sites. The incidence of autosomal fragile sites in 524 institutionalized patients with mental retardation (0.0095) was significantly higher than in 1,019 unselected neonates (0.00098). When 1 parent of an index case had the fragile site, that parent was always the mother.
Hecht and Hecht (1984) compared 21 fragile sites and 50 cancer breakpoints; 9 of the 21 fragile sites appeared in bands with a cancer breakpoint (p less than 0.001). They suggested that fragile sites may be a (the) predisposing genetic factor in familial cancer. LeBeau and Rowley (1984) reviewed the evidence suggesting that heritable fragile sites may predispose to cancer.
In a 3-year-old girl (patient 1), born of consanguineous Arabic parents, with neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities (NEDGFC; 620113), von Elsner et al. (2022) identified a homozygous 2.920-kb deletion (chr10.95,459,757_95,462,676, GRCh37) within the FRA10AC1 gene. The deletion, which was found by CNV analysis and confirmed by sequencing, encompassed the noncoding exon 1, the coding exon 2, the entire intron 1, 347 bp upstream of exon 1, and the first 30 bp of intron 2. The deletion segregated with the disorder in the family. Analysis of patient fibroblasts did not detect FRA10AC1 transcripts or protein, suggesting that the mutation triggers nonsense-mediated mRNA decay and results in a complete loss of function. The patient had a severe disease course with additional features and systemic abnormalities, including seizures, complex heart defect, displaced left kidney, and skeletal defects.
In a 9-year-old girl (patient 2), born of consanguineous Arabic parents, with neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities (NEDGFC; 620113), von Elsner et al. (2022) identified a homozygous 4-bp insertion (c.561_562insTTTA, NM_145246.5) in exon 9 of the FRA10AC1 gene, predicted to result in a frameshift and premature termination (Ser188PhefsTer6). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Analysis of patient fibroblasts did not detect FRA10AC1 transcripts or protein, suggesting that the mutation triggers nonsense-mediated mRNA decay and results in a complete loss of function. The patient had feeding difficulties, hypotonia, and profound intellectual disability.
In 3 brothers, born of consanguineous Arabic parents (family 3), with neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities (NEDGFC; 620113), von Elsner et al. (2022) identified a homozygous 3-bp in-frame deletion (c.494_496delAAG, NM_145246.5) in the FRA10AC1 gene, predicted to result in the deletion of conserved residue Glu165. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Studies of patient cells were not performed. However, HEK293 cells transfected with the mutation showed decreased levels of the mutant protein (about 19% compared to controls), suggesting instability. The mutant protein localized normally to the nucleus, although with lower signal intensity compared to wildtype. The patients had borderline to mild intellectual disability.
In 2 sisters, born of consanguineous parents (family 1), with neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities (NEDGFC; 620113), Banka et al. (2022) identified a homozygous c.328C-T transition (c.328C-T, NM145246.5) in the FRA10AC1 gene, resulting in an arg110-to-ter (R110X) substitution. The mutation was found by whole-exome sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function. The patients, who were in their twenties, had typical features of the disorder, including global development delay, poor growth, and dysmorphic features; brain imaging was not performed. One had cardiac septal defects and the other had cleft palate.
In a 12-year-old girl, born of consanguineous parents of Arabic origin (family 2), with neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities (NEDGFC; 620113), Banka et al. (2022) identified a homozygous intragenic in/del alteration in the FRA10AC1 gene, consisting of a 12-kb deletion (chr10:93,695,674_93,708,393, GRCh38) and a duplication of the first 10 bp of sequence downstream of the variant (TTAGTACACA). The 5-prime breakpoint was in the intergenic region between FRA10AC1 and LGI1 (604619) and the 3-prime breakpoint was in intron 4 of FRA10AC1. The deletion resulted in the loss of the 5-prime UTR and the first 4 exons of FRA10AC1. Patient fibroblasts showed absence of FRA10AC1 transcripts, consistent with a loss-of-function effect. RNA-seq analysis of patient fibroblasts showed a significant number of differentially expressed genes, including those that encode developmental transcription factors, compared to controls. However, there were not major changes in splicing. The patient had typical features of the disorder, with global developmental delay, late walking and speech acquisition, and feeding difficulties; brain imaging was not performed. She also had congenital heart defects and absence seizures.
In 2 sibs, born into a highly consanguineous Arab family, with neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities (NEDGFC; 620113), Alsaleh et al. (2022) identified a homozygous c.481C-T transition (c.481C-T, NM_145246.5) in exon 8 of the FRA10AC1 gene, resulting in an arg161-to-ter (R161X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found only in the heterozygous state at a low frequency in the gnomAD database (in 10 of 242,634 alleles, 0.004%). Functional studies of the variant and studies of patient cells were not performed, but it was predicted to trigger nonsense-mediated mRNA decay and result in loss of function. There was phenotypic variability: the older sib was more severely affected and died at age 6 years, whereas the younger sib was alive at age 15 months and showed milder developmental delay.
Alsaleh, N., Alhashem, A., Tabarki, B., Mohamed, S., Alharby, E., Alkuraya, F. S., Almontashiri, N. A. M. A biallelic variant in FRA10AC1 is associated with neurodevelopmental disorder and growth retardation. Neurol. Genet. 8: e200010, 2022. [PubMed: 35821753] [Full Text: https://doi.org/10.1212/NXG.0000000000200010]
Banka, S., Shalev, S., Park, S.-M., Wood, K. A., Thomas, H. B., Wright, H. L., Alyahya, M., Bankier, S., Alimi, O., Chervinsky, E., Zeef, L. A. H., O'Keefe, R. T. Bi-allelic FRA10AC1 variants in a multisystem human syndrome. Brain 145: e86-e89, 2022. [PubMed: 35871492] [Full Text: https://doi.org/10.1093/brain/awac262]
De Leon-Luis, J., Santolaya-Forgas, J., May, G., Tonk, V., Shelton, D., Galan, I. Prenatal diagnosis of FRA10A: a case report and literature review. Am. J. Med. Genet. 136A: 63-65, 2005. [PubMed: 15937938] [Full Text: https://doi.org/10.1002/ajmg.a.30093]
Hecht, F., Hecht, B. K. Autosomal fragile sites and cancer. (Letter) Am. J. Hum. Genet. 36: 718-720, 1984. [PubMed: 6428224]
LeBeau, M. M., Rowley, J. D. Heritable fragile sites in cancer. Nature 308: 607-608, 1984. [PubMed: 6709072] [Full Text: https://doi.org/10.1038/308607a0]
Sarafidou, T., Kahl, C., Martinez-Garay, I., Mangelsdorf, M., Gesk, S., Baker, E., Kokkinaki, M., Talley, P., Maltby, E. L., French, L., Harder, L., Hinzmann, B., and 25 others. Folate-sensitive fragile site FRA10A is due to an expansion of a CGG repeat in a novel gene, FRA10AC1, encoding a nuclear protein. Genomics 84: 69-81, 2004. [PubMed: 15203205] [Full Text: https://doi.org/10.1016/j.ygeno.2003.12.017]
Sutherland, G. R., Baker, E., Seshadri, R. S. Heritable fragile sites on human chromosomes. V. A new class of fragile site requiring BrdU for expression. Am. J. Hum. Genet. 32: 542-548, 1980. [PubMed: 7395866]
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von Elsner, L., Chai, G., Schneeberger, P. E., Harms, F. L., Casar, C., Qi, M., Alawi, M., Abdel-Salam, G. M. H., Zaki, M. S., Arndt, F., Yang, X., Stanley, V., Hempel, M., Gleeson, J. G., Kutsche, K. Biallelic FRA10AC1 variants cause a neurodevelopmental disorder with growth retardation. Brain 145: 1551-1563, 2022. [PubMed: 34694367] [Full Text: https://doi.org/10.1093/brain/awab403]