Molecular Pathogenesis
Cartilage and bone making up the craniofacial complex is primarily derived from neural crest cells [Trainor & Andrews 2013]. Thus, TCS features can be explained by disturbances in neural crest cell development during embryogenesis. These disturbances can be attributed to pathogenic variants in the genetic pathway activating cell development.
TCOF1, POLR1B, POLR1C, and POLR1D are all expressed in neural crest cells, and their gene products (treacle; subunits C and D for RNA polymerase I and RNA polymerase III) colocalize to the nucleolus and are involved in ribogenesis. It is hypothesized that the variants in the three key proteins are disrupting cell division by triggering p53-directed apoptosis of neuroepithelial cells [Gonzales et al 2005]. Variants affecting RNA polymerase I and/or III result in a deficiency of ribosomal RNA and/or transfer RNA [Dauwerse et al 2011], potentially leading to an insufficient number of mature ribosomes in the neuroepithelium and neural crest cells during embryogenesis [Dixon et al 2000, Dauwerse et al 2011].
POLR1B
Gene structure.
POLR1B comprises 15 coding exons, with 17 splice variants. The most common transcript contains an open reading frame of 7,527 nucleotides. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. To date, three heterozygous POLR1B pathogenic variants have been identified in five affected individuals lacking pathogenic variants in TCOF1, POLR1C, and POLR1D [Sanchez et al 2020]. These variants were all missense, two of them at the same nucleotide (c.3007C>T and c.3007C>A) in the last exon (exon 15), and one variant in exon 12 (c.2046T>A). See Table 5.
Table 5.
POLR1B Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change | Predicted Protein Change | Reference Sequences |
---|
c.2046T>A | p.Ser682Arg |
NM_019014.6
NP_061887.2
|
c.3007C>T | p.Arg1003Cys |
c.3007C>A | p.Arg1003Ser |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
POLR1B encodes the 128-kd RNA polymerase I subunit B, one of the two largest subunits (with POLR1A) that comprises the polymerase I complex. The most common isoform of the 17 transcripts codes 1,135 amino-acids.
Abnormal gene product. Pathogenic variants in POLR1B are in highly conserved amino acids in the catalytic domain of the POLR1B protein. POLR1B is associated with the POLR1A subunit of RNA polymerase. Variants may affect the hydrogen bonding that restricts interaction of the two subunits, which is suspected to cause p53-dependent apoptosis in the neuroepithelium, altering neural crest cell migration and affecting cranioskeletal formations [Sanchez et al 2020].
POLR1D
Gene structure.
POLR1D comprises three exons, with two isoforms. The longest transcript contains an open reading frame of 1,945 nucleotides with a 118-bp 5' UTR and a 1,458-bp 3' UTR. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. More than 30 heterozygous POLR1D pathogenic variants have been identified in individuals with TCS without a TCOF1 pathogenic variant [Dauwerse et al 2011, Vincent et al 2016]. These include loss-of-function (e.g., nonsense) variants, splice site and missense variants, and small deletions and duplications. Whole-gene deletions have also been described [Dauwerse et al 2011, Vincent et al 2016].
Table 6.
POLR1D Pathogenic Variants Discussed in This GeneReview
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Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Normal gene product.
POLR1D encodes the 39-kd (346-amino acid) subunit that comprises both RNA polymerase I and RNA polymerase III complexes. RNA polymerase I and RNA polymerase III are involved in ribosomal RNA transcription [Dauwerse et al 2011].
Abnormal gene product. Pathogenic variants in POLR1D lead to haploinsufficiency of POLR1D [Dauwerse et al 2011, Noack Watt et al 2016].
TCOF1
Gene structure.
TCOF1 comprises 27 coding exons, three of which are alternatively spliced in-frame (6A, 16A, and 19) [Splendore et al 2005], and an additional exon containing the 3' UTR [So et al 2004]. The longest transcript (NM_001135243.1) contains an open reading frame of 4,467 nucleotides starting in the first exon. The open reading frame is preceded by a 93-bp 5' untranslated region (UTR) and followed by a 507-bp 3' UTR [Dixon et al 1997a]. For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants. Hundreds of pathogenic variants in TCOF1 have been reported in individuals with TCS, with novel variants being identified in a significant proportion of families [Gladwin et al 1996, Treacher Collins Syndrome Collaborative Group 1996, Edwards et al 1997, Wise et al 1997, Splendore et al 2000, Ellis et al 2002, Splendore et al 2002, Dixon et al 2004, Horiuchi et al 2005, Trainor et al 2009, Bowman et al 2012, Vincent et al 2016]. The majority of pathogenic variants found to date are frameshift variants leading to a premature termination of the transcript. Pathogenic variants have been found throughout the gene.
Of TCOF1 sequencing variants, 57%-60% are small deletions or insertions, 9%-16% are splice site variants, 19%-23% nonsense variants, and 3%-4% missense variants [Bowman et al 2012, Vincent et al 2016]. Large deletions of one or more exons have also been identified in up to 5% of individuals with TCS [Beygo et al 2012, Bowman et al 2012, Vincent et al 2016]. In one case, a synonymous pathogenic TCOF1 variant led to missplicing of a constitutive exon [Macaya et al 2009].
While several pathogenic variants have occurred more than once, only one variant in TCOF1, c.4369_4373delAAGAA, has been identified as commonly recurrent. This variant is present in 16% of individuals with an identifiable pathogenic variant.
Table 7.
TCOF1 Pathogenic Variants Discussed in This GeneReview
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DNA Nucleotide Change (Alias 1) | Predicted Protein Change (Alias 1) | Reference Sequences |
---|
c.1021_1022delAG (790_791delAG) | p.Ser341GlnfsTer7 (Ser264GlnfsTer7) |
NM_001135243.1
NP_001128715.1
|
c.2490delA | p.Val831Ter |
c.2853dupT (2853_2854insT) | p.Ala952CysfsTer5 |
c.4369_4373delAAGAA | p.Lys1457GlufsTer12 |
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions
Normal gene product. The 144-kd treacle protein comprises 1,488 amino acids. Treacle is a low-complexity, three-domain nucleolar protein having unique N and C termini that is structurally related to the nucleolar phosphoprotein Nopp140 [Isaac et al 2000]. A central ten-repeat motif contains protein kinase C and casein kinase 2 phosphorylation sites [Dixon et al 1997b, Winokur & Shiang 1998]. The protein has at least two functional nuclear localization signals and a nucleolar localization signal in the C terminus. Both Nopp140 and treacle contain LIS1 motifs, leading to speculation of involvement in microtubule dynamics [Emes & Ponting 2001].
Treacle interacts with the small nucleolar ribonucleoprotein hNop56p, suggesting that it is involved in ribosomal biogenesis [Hayano et al 2003]. Treacle is involved in rDNA transcription, nucleologenesis, or trafficking of proteins or ribosomal subunits between the nucleolus and cytoplasm [Winokur & Shiang 1998, Dauwerse et al 2011]; and perhaps neural crest cell migration [Sakai & Trainor 2009, Trainor & Andrews 2013, Calo et al 2018].
Abnormal gene product. Pathogenic variants in TCOF1 lead to haploinsufficiency of the treacle protein [Isaac et al 2000]. Missense variants that allow production of an abnormal protein can disrupt either the N- or C-terminus nuclear localization signals and affect the protein's ability to transport into the nucleus during first and second branchial arch development, causing cephalic neural crest cells to undergo apoptosis during embryogenesis [Dixon et al 2000, Isaac et al 2000, Trainor & Andrews 2013]. Downregulation of TCOF1 and POLR1D leads to relocalization of DDX21, a nucleolar protein involved in ribosome biogenesis [Calo et al 2018].