Figure 2.

Clinical and Molecular Findings of Family 2

(A–C) Pedigree and clinical and radiological presentation of the patient in family 2.

(D) Identification of the homozygous donor splice-site mutation. The upper panel shows the sequence chromatogram of the index patient carrying the homozygous c.531+1G > A mutation. The dotted line represents the border between exon 2 and intron 2 of the ALX1 gene in humans. The position of domains and motifs of human ALX1 was obtained from the Uniprot database (Uniprot accession number Q15699). The amino acid sequence alignment of the homeodomains of ALX family proteins are shown in the lower panel. At the protein level, the splice site mutation targets the glutamine residue at position 177 (marked in bold) in helix III of the ALX1 homeodomain. The residues 76–177 containing a gross part of the homeodomain are encoded by exon 2. The amino acid sequence following the splice site mutation is shown in gray and is marked with a dotted arrow. The highly conserved homeodomain as well as the subsequent C-terminal parts of the protein will be affected by the splice-site mutation through different mechanisms.