Alternative titles; symbols
HGNC Approved Gene Symbol: RNU4ATAC
SNOMEDCT: 254102008, 721975004, 773404000;
Cytogenetic location: 2q14.2 Genomic coordinates (GRCh38) : 2:121,530,880-121,531,009 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q14.2 | Lowry-Wood syndrome | 226960 | Autosomal recessive | 3 |
| Microcephalic osteodysplastic primordial dwarfism, type I | 210710 | Autosomal recessive | 3 | |
| Roifman syndrome | 616651 | Autosomal recessive | 3 |
The small nuclear RNA (snRNA) U4atac is a component of the minor spliceosome and is required for the proper excision of the U12 (RNU12; 620204)-dependent class of introns (summary by He et al., 2011).
Tarn and Steitz (1996) reviewed the processing of eukaryotic precursor mRNA and noted that the majority of precursor mRNA introns contain sequences at their 5-prime and 3-prime splice sites that conform to the GU-AG consensus. They noted further that excision of these introns occurs in a large dynamic complex, the spliceosome, which is composed of U1, U2, U4-U6, and U5 small nuclear ribonucleoproteins (snRNPs) and a number of non-snRNP protein factors. The removal of a rare class of mRNA introns with AU-AC at their termini is catalyzed by a spliceosome that contains U11, U12, and U5 small nuclear ribonucleoproteins. Tarn and Steitz (1996) reported the isolation of 2 previously unidentified low-abundance human small nuclear RNAs (snRNAs), designated U4atac and U6atac (601429) by them, which are associated with the AT-AC spliceosome and are necessary for AT-AC intron splicing. U4atac exhibits only 40% sequence similarity with human U4 snRNA.
Edery et al. (2011) summarized the structure and function of the minor, or U12-dependent, spliceosome. The U12-dependent spliceosome is a ribonucleoprotein complex comprising U11 (see 610750), U12, U4atac, U5 (see 603892), and U6atac snRNAs. It is both structurally and functionally related to the U1 (see 180740), U2 (see 180690), U4, U5, and U6 (see 180692) snRNAs of the major U2-dependent spliceosome. The human genome contains approximately 700 U12-type introns removed by the minor spliceosome (Levine and Durbin, 2001; Alioto, 2007). U12-type introns are characterized by their consensus splice recognition sequences, combining a nearly invariant 5-prime splice site, either GTATCCT or ATATCCT, and a highly conserved branch site (Sharp and Burge, 1997). Most genes containing U12-type introns are either involved in key cellular functions such as DNA replication and repair, transcription, RNA processing and transport, translation, and cytoskeletal organization, or belong to a group of cellular ion channels.
The RNU4ATAC gene is located in intron 2 of the CLASP1 gene (605852) on chromosome 2q14.2 (He et al., 2011, Edery et al., 2011), -682 bp to -556 bp upstream of exon 3 (Edery et al., 2011).
Microcephalic Osteodysplastic Primordial Dwarfism Type I
He et al. (2011) identified 4 different mutations in the RNU4ATAC gene (601428.0001-601428.0004) resulting in microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) in the Ohio Amish population, 2 German families, and 1 Australian family of Maltese descent. Functional assays showed that these mutations caused defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD1 patient fibroblast cells. The introduction of wildtype U4atac snRNA into MOPD1 cells enhanced U12-dependent splicing. Using an in vivo splicing assay, He et al. (2011) showed that each mutant U4atac snRNA reduced U12-dependent splicing activity by greater than 90% compared to wildtype U4atac. The splicing defect of the genomic 51G-A mutation (601428.0001) could be corrected by complementation, suggesting that MOPD1 mutation abrogates U4atac snRNA function by disrupting the RNA secondary structure.
Edery et al. (2011) independently identified 4 mutations in the RNU4ATAC gene (601428.0001 and 601428.0005-601428.0007) responsible for MOPD1. All mutations occurred in the 5-prime stem loop structure and affected the function of the minor spliceosome. Edery et al. (2011) studied the effects of the homozygous recurrent 51G-A U4atac snRNA gene mutation on the expression of a subset of 23 genes spliced by the minor U12-dependent spliceosome and found reduced expression of several U12 genes, including DIAPH3 (614567), E2F2 (600426), GPAA1 (603048), and PHB2 (610704).
Abdel-Salam et al. (2012) reported 2 Yemeni sibs and an Egyptian boy with relatively mild MOPD1 phenotypes who were homozygous and compound heterozygous, respectively, for mutations in the RNU4ATAC gene (601428.0002 and 601428.0008-601428.0009).
Roifman Syndrome
In 6 patients from 4 families with growth retardation, cognitive delay, spondyloepiphyseal dysplasia, and antibody deficiency (RFMN; 616651), Merico et al. (2015) identified compound heterozygosity for mutations in the RNU4ATAC gene (601428.0001 and 601428.0010-601428.0015). Merico et al. (2015) noted that the patients each carried one variant overlapping MOPD1-implicated structural elements and another variant overlapping a highly conserved structural element not previously implicated in disease. RNA-seq analysis of 2 affected and 3 unaffected individuals revealed significantly higher minor intron retention in Roifman syndrome patients compared to controls, resulting in reduced levels of correctly spliced transcripts for minor intron genes; in addition, the transcriptional alterations were highly specific for minor introns. Merico et al. (2015) noted that although Roifman syndrome and MOPD1 are extremely rare, allele frequency data suggested that recessive genetic disorders caused by RNU4ATAC rare variants might be more prevalent than had been reported.
Lowry-Wood Syndrome
In a 10.75-year-old girl with Lowry-Wood syndrome (LWS; 226960), in whom previous exome sequencing had not been revealing, Farach et al. (2018) sequenced the RNU4ATAC gene and identified compound heterozygosity for 2 mutations (601428.0001 and 601428.0016). In a similarly affected sister and brother, the authors identified compound heterozygosity for another 2 mutations in RNU4ATAC (601428.0004 and 601428.0017). Farach et al. (2018) noted that MOPD1 and Roifman syndrome (RFMN; 616651), which had been considered clinically distinct from LWS although the 3 disorders share overlapping features, are also caused by biallelic mutation in the RNU4ATAC gene. Because some patients may exhibit phenotypic overlap and not fit clearly into a particular diagnosis, the authors suggested that targeted RNU4ATAC sequencing should be considered in undiagnosed patients with any combination of epiphyseal dysplasia with intellectual disability, microcephaly, immunodeficiency, and/or retinal anomalies.
In a 19-year-old patient with LWS, Shelihan et al. (2018) performed whole-exome sequencing (WES) that failed to reveal plausible candidate variants; however, following the report by Farach et al. (2018), reanalysis of the WES data identified compound heterozygosity for pathogenic variants in the RNU4ATAC gene (601428.0018 and 601428.0019). In a 28-year-old man with LWS, in whom WES was initially unfruitful, reanalysis also revealed variants in RNU4ATAC (601428.0020 and 601428.0021). Shelihan et al. (2018) noted that predicted 'fitness consequence' scores of reported RNU4ATAC variants appeared to correlate with the clinical severity of the associated disease.
Microcephalic Osteodysplastic Primordial Dwarfism
In 7 Amish patients with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710), He et al. (2011) found homozygosity for a genomic 51G-A variant within the nonprotein-coding RNU4ATAC gene. All parents were heterozygous. Haplotype analysis demonstrated that the 51G-A mutation represents a founder event in the Amish. This mutation was also found in homozygosity in an Australian patient of Maltese descent. This mutation is located within an important structural feature known as the 5-prime stem loop and was predicted to disrupt the snRNA secondary structure and cause defects in the minor spliceosome. This mutation reduced U12-dependent splicing activity by 90% relative to wildtype.
Edery et al. (2011) identified the 51G-A mutation in RNU4ATAC in homozygosity in affected members from 4 consanguineous families from the Mediterranean basin and in an Indian individual whose parents were not known to be related. Additionally, 3 unrelated patients from nonconsanguineous families carried the mutation in compound heterozygosity (see 601428.0005 and 601428.0006).
Roifman Syndrome
In a Lebanese sister and brother with Roifman syndrome (RFMN; 616651) originally reported by Gray et al. (2011), Merico et al. (2015) identified compound heterozygosity for the 51G-A transition in the RNU4ATAC gene (GenBank NR_023343) and a 16G-A transition (601428.0010), both of which involve highly conserved nucleotides in the 5-prime stem-loop critical region and the stem II region, respectively. Their unaffected parents were each heterozygous for 1 of the variants. Neither variant was found in the Complete Genomics database, but the 51G-A variant was present at a frequency of 0.0014 in the 1000 Genomes Project database and the 16G-A variant was present at a frequency of 0.0008 in the Wellderly study database.
Lowry-Wood Syndrome
In a 10.75-year-old girl (patient 1) with Lowry-Wood syndrome (LWS; 226960), Farach et al. (2018) identified compound heterozygosity for the r.51G-A transition (r.51G-A, NR_023343.1) in the RNU4ATAC gene, and an r.5A-C transversion (601428.0016) within the stem II region.
In a reportedly nonconsanguineous German family with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710), He et al. (2011) found homozygosity for a genomic 55G-A mutation in the RNU4ATAC gene. This mutation was predicted to disrupt the 5-prime stem loop of this snRNA secondary structure and cause defects in the minor spliceosome. This mutation reduced U12-dependent splicing activity by 90% relative to wildtype.
In a brother and sister with MOPD1, born of double consanguineous first-cousin parents, Abdel-Salam et al. (2012) identified homozygosity for the genomic 55G-A mutation in the RNU4ATAC gene. The authors noted that the sibs had a relatively mild MOPD1 phenotype, with developmental milestones only mildly delayed for age; however, both developed high fever and convulsions and died of encephalitis at 18 months and 34 months of age.
In a German patient with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) from a nonconsanguineous union, He et al. (2011) identified compound heterozygosity for a genomic 30G-A mutation in the RNU4ATAC gene and a 111G-A mutation (601428.0004). These mutations were predicted to disrupt the 3-prime stem loop and to interfere with the secondary structure of this snRNA and cause defects in the minor spliceosome. These mutations reduced U12-dependent splicing activity by 90% relative to wildtype.
Microcephalic Osteodysplastic Primordial Dwarfism, Type I
In a German patient with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) from a nonconsanguineous family, He et al. (2011) identified compound heterozygosity for a genomic 111G-A mutation in the RNU4ATAC gene in conjunction with a 30G-A mutation (601428.0003).
Lowry-Wood Syndrome
In a 14-year-old boy (patient 2) and his 15-year-old sister (patient 3) with Lowry-Wood syndrome (LWS; 226960), Farach et al. (2018) identified compound heterozygosity for the r.111G-A transition (r.111G-A, NR_023343.1) in the RNU4ATAC gene, and an r.46G-A transition (601428.0017).
In a patient with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) born to unrelated Caucasian parents from North America, Edery et al. (2011) identified compound heterozygosity for the common g.51G-A mutation in RNU4ATAC (601428.0001) and a g.50G-C mutation, both in the 5-prime stem loop. This patient had severe intrauterine growth retardation. Brain anomalies included agenesis of the corpus callosum, polymicrogyria, poorly developed ventricular frontal horns and lobes, and a large extra-axial fluid collection in the frontal region. Hydrocephalus developed and shunting was required. The patient died at 6 months of age.
In a patient with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) born to unrelated Norwegian parents, Edery et al. (2011) identified compound heterozygosity for the common g.51G-A mutation in RNU4ATAC (601428.0001) and a g.53C-G mutation, both in the 5-prime stem loop. The patient had brain cysts, dysmorphic features, and bone films consistent with MOPD1. The pregnancy was terminated at 16 weeks' gestation.
In a patient with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) born to unrelated Caucasian parents from North America, Edery et al. (2011) detected compound heterozygosity for the common 51G-A mutation in RNU4ATAC (601428.0001) and a G-to-A transition at genomic position 50 (50G-A). The patient had intrauterine growth retardation and microcephaly as well as agenesis of corpus callosum, polymicrogyria, poorly developed ventricular frontal horns and lobes, and a large extra-axial fluid collection in the frontal region. The patient also had hypertension and presented several fractures. He died at 6 months of age.
In an Egyptian boy with a relatively mild microcephalic osteodysplastic primordial dwarfism type I phenotype (MOPD1; 210710), Abdel-Salam et al. (2012) identified compound heterozygosity for mutations in the RNU4ATAC gene: a g.66G-C transversion and a g.124G-A transition (601428.0009). At 20 months of age, the patient's developmental milestones were only mildly delayed, with normal tone and reflexes on neurologic evaluation. He had no history of repeated infections, eczema, or seizures.
For discussion of the g.124G-A transition in the RNU4ATAC gene that was found in compound heterozygous state in a patient with relatively mild microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) by Abdel-Salam et al. (2012), see 601428.0008.
For discussion of the 16G-A transition in the RNU4ATAC gene (GenBank NR_023343) that was found in compound heterozygous state in a Lebanese sister and brother with Roifman syndrome (RFMN; 616651) by Merico et al. (2015), see 601428.0001.
In 2 brothers of Irish descent with Roifman syndrome (RFMN; 616651), previously reported by Roifman (1999), Merico et al. (2015) identified compound heterozygosity for a 13C-T transition and a 37G-A transition in the RNU4ATAC gene (GenBank NR_023343), both of which involve highly conserved nucleotides in stem II region and the 5-prime stem-loop critical region, respectively. In an Italian man with Roifman syndrome, the 13C-T variant was present in compound heterozygosity with a 48G-A transition (601428.0013) that also involves a highly conserved nucleotide in the stem II region. The unaffected parents in both families were each heterozygous for 1 of the variants. None of the variants was found in the 1000 Genomes Project or Complete Genomics databases, but the 13C-T variant was present at a frequency of 0.0008 in the Wellderly study database.
For discussion of the 37G-A transition in the RNU4ATAC gene (GenBank NR_023343) that was found in compound heterozygous state in 2 brothers with Roifman syndrome (RFMN; 616651) by Merico et al. (2015), see 601428.0011.
For discussion of the 48G-A transition in the RNU4ATAC gene (GenBank NR_023343) that was found in compound heterozygous state in an Italian man with Roifman syndrome (RFMN; 616651) by Merico et al. (2015), see 601428.0011.
In a 4-year-old Albanian boy with Roifman syndrome (RFMN; 616651), Merico et al. (2015) identified compound heterozygosity for an 8C-T transition and a 118T-C transition in the RNU4ATAC gene (GenBank NR_023343), both of which involve highly conserved nucleotides in the stem II region and the Sm protein-binding site, respectively. His unaffected parents were each heterozygous for 1 of the variants, neither of which was found in the 1000 Genomes Project or Wellderly study databases; however, the 8C-T variant was present at a frequency of 0.0011 in the Complete Genomics database.
For discussion of the 118T-C transition in the RNU4ATAC gene (GenBank NR_023343) that was found in compound heterozygous state in an Albanian boy with Roifman syndrome (RFMN; 616651) by Merico et al. (2015), see 601428.0014.
For discussion of the r.5A-C transversion (r.5A-C, NR_023343.1) in the RNU4ATAC gene, that was found in compound heterozygous state in a 10.75-year-old girl (patient 1) with Lowry-Wood syndrome (LWS; 226960) by Farach et al. (2018), see 601428.0001.
For discussion of the r.46G-A transition (r.46G-A, NR_023343.1) in the RNU4ATAC gene, that was found in compound heterozygous state in a 14-year-old boy (patient 2) and his 15-year-old sister (patient 3) with Lowry-Wood syndrome (LWS; 226960) by Farach et al. (2018), see 601428.0004. Farach et al. (2018) noted that the r.46G-A variant had previously been reported in a patient with microcephalic osteodysplastic primordial dwarfism type I (MOPD1; 210710) by Kilic et al. (2015).
In a 19-year-old patient (patient 1) with Lowry-Wood syndrome (LWS; 226960), who was originally described by Brunetti-Pierri et al. (2003), Shelihan et al. (2018) identified compound heterozygosity for an r.53C-T transition (r.53C-T, NR_023343.1) in the RNU4ATAC gene, and an r.8C-A transversion (601428.0019), located in the stem II and 5' stem-loop critical regions, respectively. The proband's unaffected parents were each heterozygous for 1 of the mutations.
For discussion of the r.8C-A transversion (r.8C-A, NR_023343.1) in the RNU4ATAC gene, that was found in compound heterozygous state in a 19-year-old patient (patient 1) with Lowry-Wood syndrome (LWS; 226960) by Shelihan et al. (2018), see 601428.0018.
In a 28-year-old man (patient 2) with Lowry-Wood syndrome (LWS; 226960), who was originally described by Magnani et al. (2009), Shelihan et al. (2018) identified compound heterozygosity for an r.120T-G transversion (r.120T-G, NR_023343.1) in the critical Sm protein-binding site of the RNU4ATAC gene, and an r.114G-C transversion (601428.0021) at a highly conserved position in the 3-prime stem-loop. His unaffected father was heterozygous for the r.120T-G variant; maternal DNA was unavailable for analysis.
For discussion of the r.114G-C transversion (r.114G-C, NR_023343.1) in the RNU4ATAC gene, that was found in compound heterozygous state in a 28-year-old man (patient 2) with Lowry-Wood syndrome (LWS; 226960) by Shelihan et al. (2018), see 601428.0020.
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