Alternative titles; symbols
HGNC Approved Gene Symbol: POLR3B
Cytogenetic location: 12q23.3 Genomic coordinates (GRCh38): 12:106,357,748-106,510,198 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q23.3 | Charcot-Marie-Tooth disease, demyelinating, type 1I | 619742 | Autosomal dominant | 3 |
| Leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism | 614381 | Autosomal recessive | 3 |
The POLR3B gene encodes the second largest subunit of RNA polymerase (pol) III. RNA polymerase III consists of 17 subunits and is involved in the transcription of small noncoding RNAs, such as 5S ribosomal RNA (180420), U6 small nuclear RNA (see 180692), and short interspersed nuclear elements (SINEs), as well as all transfer RNAs (summary by Saitsu et al., 2011).
Using mass spectrometry to identify peptides obtained from purified HeLa cell RNA polymerase III complexes, followed by EST database analysis and PCR of a HeLa cell cDNA library, Hu et al. (2002) cloned human POLR3B, which they called RPC2. The deduced 1,133-amino acid protein has a calculated molecular mass of 128 kD. It contains a zinc-binding domain near its C terminus that is predicted to form part of a clamp structure. Human RPC2 shares 63% amino acid identity with S. cerevisiae Rpc2 and 38% identity with the second largest subunit of human RNA polymerase II, RPB2 (POLR2B; 180661).
Hartz (2011) mapped the POLR3B gene to chromosome 12q23.3. based on an alignment of the POLR3B sequence (GenBank AK001250) with the genomic sequence (GRCh37).
Hypomyelinating Leukodystrophy 8
Using whole-exome sequencing, Saitsu et al. (2011) identified compound heterozygous mutations in the POLR3B gene (614366.0001-614366.0004) in 3 patients from 2 unrelated Japanese families with hypomyelinating leukodystrophy-8 (HLD8; 614381). Two of the patients had hypogonadotropic hypogonadism, but none had hypodontia.
In 3 unrelated patients of European descent with HLD8, Tetreault et al. (2011) identified compound heterozygous mutations in the POLR3B gene (614366.0005-614366.0008). All had hypodontia and 2 developed hypogonadotropic hypogonadism.
Daoud et al. (2013) identified compound heterozygous mutations in the POLR3B gene in 7 patients with HLD8. Of the 8 mutations identified, 7 were novel (see, e.g., 614366.0016-614366.0018). Six patients carried the previously identified V523E mutation (614366.0005), which was located on a shared common haplotype in all 6.
In a 15-year-old boy with HLD8, Ghoumid et al. (2017) identified compound heterozygous mutations in the POLR3B gene: the recurrent V523E mutation and a missense mutation (P925Q; 614366.0015).
In a 21-year-old woman with HLD8, Verberne et al. (2020) identified homozygosity for the recurrent V523E mutation in the POLR3B gene.
Demyelinating Charcot-Marie-Tooth Disease Type 1I
In 6 unrelated patients with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; 619742), Djordjevic et al. (2021) identified de novo heterozygous missense mutations in the POLR3B gene (see, e.g., 614366.0009-614366.0012). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variants showed that 5 of the 6 impaired the association of POLR3B with one or more of the other RNA pol III subunits; the sixth variant showed disrupted association of POLR3B with multiple proteins. These findings suggested that the most of the mutations would render the enzyme inactive. All of the variants localized properly to the nucleus. Western blot analysis of fibroblasts from 1 patient showed normal protein expression. The authors postulated a dominant-negative effect, but noted that more studies were needed to confirm the pathogenetic mechanism.
In a 19-year-old Chinese man with CMT1I, Xue et al. (2021) identified a de novo heterozygous R1046H mutation at a highly conserved residue in the POLR3B gene. The mutation, which was found by exome sequencing, was absent from public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. He had normal cognition and no evidence of central nervous system involvement.
Associations Pending Confirmation
For discussion of a possible association between Wiedemann-Rautenstrauch syndrome (see 264090) and variation in the POLR3B gene, see 614366.0013.
In 2 Japanese adult sibs, born of unrelated parents, with hypomyelinating leukodystrophy-8 with hypogonadotropic hypogonadism (HLD8; 614381), Saitsu et al. (2011) identified compound heterozygosity for 2 mutations in the POLR3B gene: a paternally inherited A-to-C transversion in intron 17, resulting in a splice site mutation, and a maternally inherited 2303G-A transition in exon 21, resulting in an arg768-to-his (R768H; 614366.0002) substitution in a highly conserved residue. The splice site mutation was shown to cause a deletion of exon 18 and an in-frame 33-amino acid deletion (Asn620_Lys652del). Modeling with the yeast homolog of the pol II subunit indicated that the deletion would destroy a structural core of the protein, leading to loss of function. Yeast modeling also suggested that arg768 interacts with the main-chain carbonyl groups in other subunits, and that the R768H substitution would disturb these interactions and cause polymerase dysfunction. The R768H mutation was found in 1 of 540 Japanese control chromosomes, and the splice site mutation was not found in control chromosomes. After normal early infantile development, the patients presented with walking and exercise difficulties at age 3 years. They had mild intellectual disability but were able to finish high school. As adults, both had cerebellar signs, including ataxic speech, wide-based ataxic gait, dysdiadochokinesis, and dysmetria, hypotonia, and mild hyperreflexia without extensor plantar responses. Both also showed signs of hypogonadotropic hypogonadism, but did not have hypodontia. Other features included myopia, mild horizontal nystagmus, slowing of smooth-pursuit eye movements, and vertical gaze limitation. Brain MRI showed high-intensity areas in the white matter on T2-weighted images, consistent with diffuse cerebral hypomyelination, as well as cerebellar atrophy, and hypoplastic corpus callosum.
For discussion of the arg768-to-his (R768H) mutation in the POLR3B gene that was found in compound heterozygous state in 2 sibs with hypomyelinating leukodystrophy-8 with hypogonadotropic hypogonadism (HLD8; 614381) by Saitsu et al. (2011), see 614366.0001.
In a 16-year-old Japanese girl with hypomyelinating leukodystrophy-8 (HLD8; 614381), previously reported as patient 1 by Sasaki et al. (2009), Saitsu et al. (2011) identified compound heterozygosity for 2 mutations in the POLR3B gene: a paternally inherited 1648C-T transition in exon 16, resulting in an arg550-to-ter (R550X) substitution, and a maternally inherited 2778C-G transversion in exon 24, resulting in an asp926-to-glu (D926E; 614366.0004) substitution in a highly conserved residue. The R550X transcript was shown to undergo nonsense-mediated mRNA decay. Modeling with the yeast homolog of the pol II subunit suggested that asp926 interacts with the main-chain carbonyl groups in other subunits, and that the D926E substitution would disturb these interactions and cause polymerase dysfunction. Neither mutation was found in 540 Japanese control chromosomes. The patient began to walk unsteadily at age 11 months but retained her ability to walk as a teen. She had cerebellar signs, mild spasticity, slowing of smooth-pursuit eye movements, vertical gaze limitations, and intellectual disability. She did not have hypogonadism or hypodontia.
For discussion of the asp926-to-glu (D926E) mutation in the POLR3B gene that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 (HLD8; 614381) by Saitsu et al. (2011), see 614366.0003.
In 3 unrelated patients of European descent with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381), Tetreault et al. (2011) identified compound heterozygous mutations in the POLR3B gene. All had a heterozygous 1568T-A transversion in exon 15, resulting in a val523-to-glu (V523E) substitution. The other POLR3B mutations found in compound heterozygosity with V523E were a 1508C-A transversion in exon 15, resulting in a thr503-to-lys (T503K; 614366.0006) substitution; a 1-bp deletion (1533delT; 614366.0007) predicted to result in a frameshift and premature stop codon; and a 2686A-T transversion in exon 23, resulting in a lys896-to-ter (K896X; 614366.0008) substitution. Based on electron microscopy structure, the V523E and T503K substitutions were predicted be located near the 'jaw' of pol III, where other subunits are localized. Thus these mutations would affect local structure and impair proper function of pol III. None of the mutations were found in 340 control chromosomes, except for V523E, which was found in 2 (0.5%) of 374 control chromosomes. All patients presented in early childhood with mild developmental delays and developed dysarthria as well as progressive motor difficulties, including cerebellar ataxia. Two showed progressive spasticity. Two individuals developed hypogonadotropic hypogonadism, whereas the third was too young to evaluate for endocrine dysfunction. All 3 individuals had teeth abnormalities, such as neonatal upper incisors, delayed eruption of deciduous teeth and permanent teeth, abnormal sequence of eruption, and malposition. Brain MRI showed thin corpus callosum, cerebellar atrophy, and hypomyelination.
Wolf et al. (2014) reported that 51 of 62 patients with HLD8 were compound heterozygous for the V523E variant and another mutation in the POLR3B gene. Only 1 sib pair was homozygous for V523E, and the sibs had an exceptionally mild clinical course, with the older sib having no neurologic signs at age 21 years. Brain MRI in the sibs showed much better myelination in the 2 homozygous sibs than in the other patients.
In 2 unrelated patients (patients 8 and 9) with HLD8, Daoud et al. (2013) identified compound heterozygous mutations in the POLR3B gene: V523E and a c.2084-6A-G transition (IVS19-6A-G; 614366.0016) in intron 19, resulting in creation of a cryptic splice site and leading to a frameshift and premature termination (Gly695ValfsTer5). The mutations were identified by sequencing of the POLR3B gene. The V523E variant had an allele frequency of 0.5% in the dbSNP database.
In a 15-year-old boy with HLD8, Ghoumid et al. (2017) identified compound heterozygous mutations in the POLR3B gene: V523E and a c.2274T-C transition resulting in a pro925-to-gln (P925Q; 614366.0015) substitution at a conserved site. The mutations were identified by Sanger sequencing of the POLR3B gene. The P925Q mutation was predicted to modify protein conformation. It was not present in the ExAC database.
In a 21-year-old Dutch Caribbean woman with HLD8, Verberne et al. (2020) identified homozygosity for the V523E mutation. The mutation was found by sequencing of a gene panel of 761 genes associated with intellectual disability. Both parents were heterozygous for the mutation. The mutation was present in the gnomAD database at an allele frequency of 0.0003%. The patient had ataxia, developmental delay, and impaired intellectual development.
For discussion of the thr503-to-lys (T503K) mutation in the POLR3B gene that was found in compound heterozygous state in patients with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Tetreault et al. (2011), see 614366.0005.
For discussion of the 1-bp deletion in the POLR3B gene (1533delT) that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Tetreault et al. (2011), see 614366.0005.
For discussion of the lys896-to-ter (K896X) mutation in the POLR3B gene that was found in compound heterozygous state in patients with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Tetreault et al. (2011), see 614366.0005.
In a 16-year-old girl (patient 1) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; 619742), Djordjevic et al. (2021) identified a de novo heterozygous c.1124A-T transversion (c.1124A-T, NM_018082.5) in the POLR3B gene, resulting in an asp375-to-val (D375V) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Western blot analysis of patient fibroblasts showed normal protein levels. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with other RNA pol III subunits. These findings suggested that the variant would render the enzyme inactive; the authors postulated a dominant-negative effect. The patient had peripheral neuropathy, global developmental delay, ataxia, and progressive spasticity.
In a 11-year-old boy (patient 3) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; 619742), Djordjevic et al. (2021) identified a de novo heterozygous c.3137G-A transition (c.3137G-A, NM_018082.5) in the POLR3B gene, resulting in an arg1046-to-his (R1046H) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with other RNA pol III subunits. These findings suggested that the variant would render the enzyme inactive; the authors postulated a dominant-negative effect. The patient had peripheral sensorimotor neuropathy with no central nervous system involvement; development and cognition were normal.
In a 19-year-old Chinese man with CMT1I, Xue et al. (2021) identified a de novo heterozygous R1046H mutation at a highly conserved residue in the POLR3B gene. The mutation, which was found by exome sequencing, was absent from public databases, including gnomAD. Functional studies of the variant and studies of patient cells were not performed. The patient developed progressive muscle weakness and atrophy of the lower limbs starting at age 5 years. Electrophysiologic studies were consistent with a sensorimotor demyelinating polyneuropathy with secondary axonal loss, consistent with CMT. He had normal cognition and no evidence of central nervous system involvement.
In a 22-year-old man (patient 4) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; 619742), Djordjevic et al. (2021) identified a de novo heterozygous c.1094C-T transition (c.1094C-T, NM_018082.5) in the POLR3B gene, resulting in an ala365-to-val (A365V) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with other RNA pol III subunits. These findings suggested that the variant would render the enzyme inactive; the authors postulated a dominant-negative effect. In addition to a peripheral neuropathy, the patient had global developmental delay, progressive spasticity, and early-onset refractory epilepsy.
In an 8-year-old girl (patient 5) with demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I; 619742), Djordjevic et al. (2021) identified a de novo heterozygous c.1087G-A transition (c.1087G-A, NM_018082.5) in the POLR3B gene, resulting in a glu363-to-lys (E363K) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Affinity purification coupled with mass spectrometry performed on HEK293 cells transfected with the variant showed that it impaired the association of POLR3B with multiple other proteins. The authors postulated a dominant-negative effect. The patient had peripheral neuropathy, global developmental delay, ataxia, and progressive spasticity.
This variant is classified as a variant of unknown significance because its contribution to Wiedemann-Rautenstrauch syndrome (see 264090) has not been confirmed.
In a 6-year-old Italian boy diagnosed with Wiedemann-Rautenstrauch syndrome, Wu et al. (2021) identified compound heterozygous mutations in the POLR3B gene: a c.2191G-C transversion (c.2191G-C, NM_018082.5), resulting in a glu731-to-gln (E731Q) substitution, and a c.3046G-A transition, resulting in a val1016-to-met (V1016M; 614366.0014) substitution. The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were found in the carrier state in both parents. Neither mutation was present in the 1000 Genomes Project and gnomAD databases. Both mutations are located at highly conserved sites in the RNA_pol_Rpb2_6 domain. No functional studies were reported. The patient had progeroid features, micrognathia, triangular facies, macrocephaly, loss of subcutaneous fat, sparse hair, congenital dislocation of the hip, and hallux valgus. A subsequent sib pregnancy was terminated with the fetus having features of a lemon-shaped brain with a small frontal lobe. The fetus also was found to have the W731Q and V1016M mutations in the POLR3B gene.
This variant is classified as a variant of unknown significance because its contribution to Wiedemann-Rautenstrauch syndrome (see 264090) has not been confirmed.
For discussion of the c.3046G-A transition (c.3046G-A, NM_018082.5) in the POLR3B gene, resulting in a val1016-to-met (V1016M) substitution, that was found in compound heterozygous state in a patient diagnosed with Wiedemann-Rautenstrauch syndrome by Wu et al. (2021), see 614366.0013.
For discussion of the c.2774C-A transversion (c.2774C-A, NM_018082.5) in the POLR3B gene, resulting in a pro925-to-gln (P925Q) substitution, that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Ghoumid et al. (2017), see 614366.0005.
For discussion of the c.2084-6A-G mutation in the POLR3B gene, resulting in a frameshift and premature termination (Gly695fsTer5) that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Daoud et al. (2013), see 614366.0005.
In a patient (patient 13) with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381), Daoud et al. (2013) identified compound heterozygous mutations in the POLR3B gene: a c.312G-T transversion (c.312G-T, NM_018082) in exon 6, resulting in a leu104-to-phe (L104F) substitution, and a c.2570+1G-A transition (614366.0018) in intron 22, resulting in a frameshift and premature termination (Gly818fsAlaTer13). Analysis of RNA from patient lymphoblastoid cells showed that the mutation resulted in skipping of exon 22. The mutations were identified by sequencing of the POLR3B gene. Neither mutation was present in the dbSNP database.
For discussion of the c.2570+1G-A transition (c.2570+1G-A, NM_018082) in intron 22 of the POLR3B gene, resulting in a frameshift and premature termination (Gly818fsTer13), that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-8 with hypodontia and hypogonadotropic hypogonadism (HLD8; 614381) by Daoud et al. (2013), see 614366.0017.
Daoud, H., Tetreault, M., Gibson, W., Guerrero, K., Cohen, A., Gburek-Augustat, J., Synofzik, M., Brais, B., Stevens, C. A., Sanchez-Carpintero, R., Goizet, C., Naidu, S., Vanderver, A., Bernard, G. Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism. J. Med. Genet. 50: 194-197, 2013. [PubMed: 23355746] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101357]
Djordjevic, D., Pinard, M., Gauthier, M.-S., Smith-Hicks, C., Hoffman, TL., Wolf, NI., Oegema, R., van Binsbergen, E., Baskin, B., Bernard, G., Fribourg, S., Coulombe, B., Yoon, G. De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy. Am. J. Hum. Genet. 108: 186-193, 2021. Note: Erratum: Am. J. Hum. Genet. 109: 759-763, 2022. [PubMed: 33417887] [Full Text: https://doi.org/10.1016/j.ajhg.2020.12.002]
Ghoumid, J., Petit, F., Boute-Benejean, O., Frenois, F., Cartigny, M., Vanlerberghe, C., Smol, T., Caumes, R., de Roux, N., Manouvrier-Hanu, S. Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder. Europ. J. Hum. Genet. 25: 1011-1014, 2017. [PubMed: 28589944] [Full Text: https://doi.org/10.1038/ejhg.2017.73]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/29/2011.
Hu, P., Wu, S., Sun, Y., Yuan, C.-C., Kobayashi, R., Myers, M. P., Hernandez, N. Characterization of human RNA polymerase III identifies orthologues for Saccharomyces cerevisiae RNA polymerase III subunits. Molec. Cell. Biol. 22: 8044-8055, 2002. [PubMed: 12391170] [Full Text: https://doi.org/10.1128/MCB.22.22.8044-8055.2002]
Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N. Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. Am. J. Hum. Genet. 89: 644-651, 2011. [PubMed: 22036171] [Full Text: https://doi.org/10.1016/j.ajhg.2011.10.003]
Sasaki, M., Takanashi, J., Tada, H., Sakuma, H., Furushima, W., Sato, N. Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum. Brain Dev. 31: 582-587, 2009. [PubMed: 18851904] [Full Text: https://doi.org/10.1016/j.braindev.2008.09.003]
Tetreault, M., Choquet, K., Orcesi, S., Tonduti, D., Balottin, U., Teichmann, M., Fribourg, S., Schiffmann, R., Brais, B., Vanderver, A., Bernard, G. Recessive mutations in POLR3B, encoding the second largest subunit of pol III, cause a rare hypomyelinating leukodystrophy. Am. J. Hum. Genet. 89: 652-655, 2011. [PubMed: 22036172] [Full Text: https://doi.org/10.1016/j.ajhg.2011.10.006]
Verberne, E. A., Dalen Meurs, L., Wolf, N. I., 4H leukodystrophy caused by a homozygous POLR3B mutation. further delineation of the phenotype. Am. J. Med. Genet. 182A: 1776-1779, 2020. [PubMed: 32319736] [Full Text: https://doi.org/10.1002/ajmg.a.61600]
Wolf, N. I., Vanderver, A., van Spaendonk, R. M. L., Schiffmann, R., Brais, B., Bugiani, M., Sistermans, E., Catsman-Berrevoets, C., Kros, J. M., Soares Pinto, P., Pohl, D., Tirupathi, S., and 10 others. Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations. Neurology 83: 1898-1905, 2014. [PubMed: 25339210] [Full Text: https://doi.org/10.1212/WNL.0000000000001002]
Wu, S.-W., Li, L., Feng, F., Wang, L., Kong, Y.-Y., Liu, X.-W., Yin, C. Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome. Ital. J. Pediat. 47: 160, 2021. [PubMed: 34289880] [Full Text: https://doi.org/10.1186/s13052-021-01112-6]
Xue, Y.-Y., Cheng, H.-L., Dong, H.-L., Yin, H.-M., Yuan, Y., Meng, L.-C., Wu, Z.-Y., Yu, H. A de novo variant of POLR3B causes demyelinating Charcot-Marie-Tooth disease in a Chinese patient: a case report. BMC Neurol. 21: 402, 2021. [PubMed: 34666706] [Full Text: https://doi.org/10.1186/s12883-021-02399-y]