Figure 2.

Two NDE1 Mutations Identified within an Overlapping Region of Homozygosity in Both Pedigrees on Chromosome 16

(A) Homozygosity analysis of both pedigrees identified a 4.6 Mb region on chromosome 16 that is homozygous in all three affected children. All homozygous SNPs are represented as blue, and heterozygous SNPs are represented as yellow. The maximal LOD scores of the two pedigrees at the homozygous region are 1.8 and 1.2, respectively. The shared region of homozygosity contains approximately 35 annotated genes, including NDE1.

(B) Human NDE1 consists of nine exons (eight coding exons), which encode a protein with 335 amino acids harboring multiple protein-interaction domains. Two frameshift mutations were indentified in exons 6 and 7, respectively; both are predicted to disrupt the CENP-F, dynein interaction domain, centrosomal localization domain, and at least two conserved phosphorylation residues implicated in mitotic progression (T246 and S250) at the C terminus. The black bars show noncoding exons; open bars show coding exons. The red dots indicate potential phosphorylation sites.

(C) Representative Sanger sequencing traces indicating the two base-pair deletions identified in patient 08DG00536 (family 1, IV-2 in Figure 1A) and the one base-pair duplicated identified in patient MC-14901 (family 2, II-7 in Figure 1A).