Genomic structure of karyopherin α2 (KPNA2) within a low-copy repeat on chromosome 17q23-q24 and mutation analysis in patients with Russell-Silver syndrome

Abstract.

Human karyopherin α2 (KPNA2), a member of the karyopherin α family, plays a key role in the nuclear import of proteins with a classical nuclear localization signal (NLS). KPNA2, as part of a karyopherin α-β heterodimer, directly binds to the NLS of proteins and functions as an adaptor that binds NLS-containing proteins via karyopherin β to the nuclear pore complex. The NLS protein-receptor complex is translocated through the pore by an energy-dependent mechanism. Recently, we have identified and mapped the gene for KPNA2 in close proximity to a translocation breakpoint within 17q23-q24 associated with Russell-Silver syndrome (RSS). Therefore, we considered KPNA2 as a positional candidate gene for this heterogeneous disorder. RSS is mainly characterized by pre- and postnatal growth retardation, lateral asymmetry, and other dysmorphic features. Here, we present the genomic organization of the human KPNA2 gene with 11 exons spanning approximately 10 kb on chromosome 17q23-q24. Screening for mutations within all exons and adjacent intronic sequences from 31 unrelated RSS patients revealed three single nucleotide polymorphisms (SNPs) in exons 1, 5, and 7, and five SNPs in introns 1, 4 (2 SNPs), 8, and 9, respectively. No disease-related mutation was identified by comparing the sequence data of the RSS patients with their clinically normal parents and controls.