Extensive molecular genetic analysis of the 3p14.3 region in patients with Zimmermann-Laband syndrome.

Zimmermann-Laband syndrome (ZLS) is a rare autosomal dominant inherited disorder characterized by a coarse facial appearance, gingival fibromatosis, and absence or hypoplasia of the terminal phalanges and nails of hands and feet. Additional, more variable features include hyperextensibility of joints, hepatosplenomegaly, mild hirsutism, and mental retardation. Mapping of the translocation breakpoints of t(3;8) and t(3;17) found in patients with the typical clinical features of ZLS defined a common breakpoint region of approximately 280 kb located in 3p14.3, which includes the genes CACNA2D3 and WNT5A. Breakpoint cloning revealed that both translocations most likely occurred by non-homologous (illegitimate) recombination. Mutation analysis of nine genes located in 3p21.1-p14.3, including CACNA2D3, which is directly disrupted by one breakpoint of the t(3;17), identified no pathogenic mutation in eight sporadic patients with ZLS. Southern hybridization analysis and multiplex ligation-dependent probe amplification (MLPA) did not detect submicroscopic deletion or duplication in either CACNA2D3 or WNT5A in ZLS-affected individuals. Mutation analysis of nine conserved nongenic sequence elements (CNEs) in 3p21.1-p14.3, which were identified by interspecies comparison and may represent putative regulatory elements for spatiotemporally correct expression of nearby genes, did not show any sequence alteration associated with ZLS. Taken together, the lack of a specific coding-sequence lesion in the common region, defined by two translocation breakpoints, in sporadic patients with ZLS and an apparently normal karyotype suggests that either some other type of genetic defect in this vicinity or an alteration elsewhere in the genome could be responsible for ZLS.