Volume 89, Issue 5, Pages (May 1997)

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Volume 89, Issue 5, Pages 773-779 (May 1997) Mutations Involving the Transcription Factor CBFA1 Cause Cleidocranial Dysplasia S Mundlos, F Otto, C Mundlos, J.B Mulliken, A.S Aylsworth, S Albright, D Lindhout, W.G Cole, W Henn, J.H.M Knoll, M.J Owen, R Mertelsmann, B.U Zabel, B.R Olsen Cell Volume 89, Issue 5, Pages 773-779 (May 1997) DOI: 10.1016/S0092-8674(00)80260-3

Figure 1 Ten-Year-Old Boy with Failed Closure of Anterior/Posterior Fontanelles and Sagittal Suture Note multiple parietal Wormian bones. Cell 1997 89, 773-779DOI: (10.1016/S0092-8674(00)80260-3)

Figure 2 Physical Map of CCD Locus, Deletions in Three CCD Pedigrees, Location and Exon Structure of CBFA1 Gene, and Amino Acid Sequence of CBFA1 (A) Overlapping YAC clones covering CCD locus. Markers used to map locus and order YACs are shown at top of figure. Known genes (MUT, CBFA1, and TCTE1) that mapped to YAC contig are indicated in bold. -NL and -NR refer to cloned and sequenced end regions of specific YACs used for ordering. Telomere is to right and centromere is to left. (B) Deleted regions in family O (CCD-O) and in patients H (CCD-H) and M (CCD-M) have similar distal boundaries. Proximal boundary of CCD-H deletion not tested and should be considered tentative. (C) Location of CBFA1 relative to YAC contig and exon structure of gene. Six PACs covering entire gene are indicated. runt domain in CBFA1 is encoded by exons 1–3 (exons counted from 5′ end of gene). Exon 0 contains an alternative translation start site. (D) Numbers on left indicate amino acids in translated sequence counted from methionine residue in exon 1. Amino acid sequence of runt domain underlined. The alternative translation start and N-terminal sequence in exon 0 are shown on top. Affected son of family CCD-J has G-to-A transition at codon 283 (corresponding tryptophan residue is underlined) that converts TGG codon to TGA (stop) codon. Cell 1997 89, 773-779DOI: (10.1016/S0092-8674(00)80260-3)

Figure 3 Analyses of Mutant Regions in CCD Pedigrees (A) Gel analyses of PCR-amplified mutant regions in pedigrees CCD-B, CCD-G, and CCD-J. Larger band (arrow) in affected members of CCD-B represents in-frame duplication of 30 bp within the polyalanine region of CBFA1. Spouse of an affected family member and his son show additional shorter band (triangles) identified as a polymorphic 18 bp deletion within polyalanine region. Affected daughter of family CCD-G has a 16 bp insertion within polyglutamine region; parents have only wild-type allele. Affected son in family CCD-J has G-to-A transition in codon 283. This nucleotide change creates a new restriction site for MboI, which cuts PCR-amplified sequence of affected allele into two fragments (arrows); amplified DNA from unaffected parents is not cut. Molecular weight size markers shown on right. (B) Frame-shift mutation in polyglutamine stretch in family CCD-G. Mutant sequence differs from that of wild type in that nt 145–162 (counted from methionine residue in exon 1) are replaced by a longer sequence (bottom). Comparison of the positions of CAA codons (indicated by boxes) in wild type and mutant sequences suggests that mutation involved duplication of sequence between nt 130 and 159 (indicated by horizontal line) and addition of CCGG tetranucleotide. (C) Frame-shift mutation in runt domain in CCD-R. Deletion of 10 nt between nt 497 and 506 causes stop codon downstream of mutation. (D) Nucleotide and amino acid sequence of polyalanine stretch in CBFA1. Imperfections in GCG repeats indicated in bold letters. The 18 bp deletion leading to 11 alanine polymorphism is underlined. The 30 bp duplication in family CCD-B and possible insertion point are shown below. Cell 1997 89, 773-779DOI: (10.1016/S0092-8674(00)80260-3)

Figure 4 Radiographs of Clavicle and Hands of Affected Individuals in Family CCD-B (A) Left shoulder region with distal gap in clavicle (arrow). (B) Affected child with prominent brachydactyly: distal phalanges are hypoplastic and middle phalanges have cone-shaped epiphyses (arrows). Metacarpals exhibit pseudoepiphyses and shortening of metacarpals IV and V (open arrow). Cell 1997 89, 773-779DOI: (10.1016/S0092-8674(00)80260-3)