Figure 1.
A resource of mutations identified in ICF syndrome. Schematic comprehensive representation of the mutations described in ICF syndrome patients, mapped to the protein sequence, for DNMT3B or ICF1 (genomic location: chr20; protein isoform: NP_008823.1), ZBTB24 or ICF2 (genomic location: chr6; protein isoform: NP_055612.1), CDCA7 or ICF3 (genomic location: chr2; protein isoform: NP_665809.1), and HELLS or ICF4 (genomic location: chr10; protein isoform: NP_060533.2). Information on mutations, protein structures, and their locations was collected from ClinVar (20), UniProt (21, 22), InterPro (22), icn3d (23), and Atlas of Genetics and Cytogenetics in Oncology and Haematology (24), and the respective reference studies (DNMT3B [5, 7, 10, 11, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46], ZBTB24 [7, 8, 11, 17, 32, 33, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59], CDCA7 [18], and HELLS [18, 30, 60]). Missense mutations are represented in black, nonsense mutations in red, frameshifts in green, intron mutations in blue, and deletions in purple. Dashed lines represent mutations identified in heterozygosity, and solid lines mutations in homozygosity. Some mutations have been described in both heterozygosity and homozygosity in different patients, e.g., p.Ala603Thr in DNMT3B. The genetic variant notations used were collected from ClinVar and from the original studies, if a ClinVar entry was non-existing; furthermore, the notations from CDCA7 and HELLS were collected exclusively from (18). DNMT3B harbors the following annotated domains: ATRX-Dnmt3-Dnmt3L (ADD) and PWWP at N terminus that mediate chromatin reading and binding through interactions with histone modifications, and the C-terminal catalytic domain SAM-dependent MTase C5-type, which includes six conserved motifs (I, IV, VI, VIII, IX, and X). ZBTB24 is composed at N terminus by a BTB domain, involved in oligomerization and/or dimerization, and AT-hook domain, which binds to AT-rich DNA sequences, as well as eight C2H2-type zinc-finger domains in the C terminus that mediate the transcription factor function through sequence-specific DNA recognition. CDCA7 interacts with MYC and 14-3-3 proteins via a specific domain at its N terminus and the C-terminal zinc-finger domain (4CXXC) is required for recognition of DNA sequences rich in hemimethylated CpGs. HELLS possesses an N-terminal SNF2 family helicase ATP-binding, an ATPase domain responsible for mediation of nucleosome sliding and chromatin remodeling, and a C-terminal helicase motif.

A resource of mutations identified in ICF syndrome. Schematic comprehensive representation of the mutations described in ICF syndrome patients, mapped to the protein sequence, for DNMT3B or ICF1 (genomic location: chr20; protein isoform: NP_008823.1), ZBTB24 or ICF2 (genomic location: chr6; protein isoform: NP_055612.1), CDCA7 or ICF3 (genomic location: chr2; protein isoform: NP_665809.1), and HELLS or ICF4 (genomic location: chr10; protein isoform: NP_060533.2). Information on mutations, protein structures, and their locations was collected from ClinVar (20), UniProt (21, 22), InterPro (22), icn3d (23), and Atlas of Genetics and Cytogenetics in Oncology and Haematology (24), and the respective reference studies (DNMT3B [5, 7, 10, 11, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46], ZBTB24 [7, 8, 11, 17, 32, 33, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59], CDCA7 [18], and HELLS [18, 30, 60]). Missense mutations are represented in black, nonsense mutations in red, frameshifts in green, intron mutations in blue, and deletions in purple. Dashed lines represent mutations identified in heterozygosity, and solid lines mutations in homozygosity. Some mutations have been described in both heterozygosity and homozygosity in different patients, e.g., p.Ala603Thr in DNMT3B. The genetic variant notations used were collected from ClinVar and from the original studies, if a ClinVar entry was non-existing; furthermore, the notations from CDCA7 and HELLS were collected exclusively from (18). DNMT3B harbors the following annotated domains: ATRX-Dnmt3-Dnmt3L (ADD) and PWWP at N terminus that mediate chromatin reading and binding through interactions with histone modifications, and the C-terminal catalytic domain SAM-dependent MTase C5-type, which includes six conserved motifs (I, IV, VI, VIII, IX, and X). ZBTB24 is composed at N terminus by a BTB domain, involved in oligomerization and/or dimerization, and AT-hook domain, which binds to AT-rich DNA sequences, as well as eight C2H2-type zinc-finger domains in the C terminus that mediate the transcription factor function through sequence-specific DNA recognition. CDCA7 interacts with MYC and 14-3-3 proteins via a specific domain at its N terminus and the C-terminal zinc-finger domain (4CXXC) is required for recognition of DNA sequences rich in hemimethylated CpGs. HELLS possesses an N-terminal SNF2 family helicase ATP-binding, an ATPase domain responsible for mediation of nucleosome sliding and chromatin remodeling, and a C-terminal helicase motif.

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