Klippel-Feil syndrome: clinical features and current understanding of etiology.

Klippel-Feil syndrome occurs in a heterogeneous group of patients unified only by the presence of a congenital defect in the formation or segmentation of the cervical spine. Numerous associated abnormalities of other organ systems may be present. This heterogeneity requires comprehensive evaluation of all patients and treatment regimes that can vary from modification of activities to extensive spinal surgeries. This also has made delineation of diagnostic and prognostic classes difficult and has complicated elucidation of the genetic etiology of the syndrome. Furthermore, it is unclear whether Klippel-Feil syndrome is a discrete entity, or if it is one point on a spectrum of congenital spinal deformities. Pedigree analysis has identified a human genetic locus for the disease. Mouse models suggest members of the PAX gene family and Notch signaling pathway as possible etiologic candidates. Only by identifying the link between the genetic etiology and the phenotypic pathoanatomy of Klippel-Feil syndrome will we be able to rationalize the heterogeneity of the syndrome.

Evolutionary history of the enolase gene family.

The enzyme enolase [EC 4.2.1.11] is found in all organisms, with vertebrates exhibiting tissue-specific isozymes encoded by three genes: alpha (alpha), beta (beta), and gamma (gamma) enolase. Limited taxonomic sampling of enolase has obscured the timing of gene duplication events. To help clarify the evolutionary history of the gene family, cDNAs were sequenced from six taxa representing major lineages of vertebrates: Chiloscyllium punctatum (shark), Amia calva (bowfin), Salmo trutta (trout), Latimeria chalumnae (coelacanth), Lepidosiren paradoxa (South American lungfish), and Neoceratodus forsteri (Australian lungfish). Phylogenetic analysis of all enolase and related gene sequences revealed an early gene duplication event prior to the last common ancestor of living organisms. Several distantly related archaebacterial sequences were designated as 'enolase-2', whereas all other enolase sequences were designated 'enolase-1'. Two of the three isozymes of enolase-1, alpha- and beta-enolase, were discovered in actinopterygian, sarcopterygian, and chondrichthian fishes. Phylogenetic analysis of vertebrate enolases revealed that the two gene duplications leading to the three isozymes of enolase-1 occurred subsequent to the divergence of living agnathans, near the Proterozoic/Phanerozoic boundary (approximately 550Mya). Two copies of enolase, designated alpha(1) and alpha(2), were found in the trout and are presumed to be the result of a genome duplication event.