RESUMO
Studies of genetically engineered flies and mice have revealed the role that orthologs of the human LIM homeobox LHX4 have in the control of motor-neuron-identity assignment and in pituitary development. Remarkably, these mouse strains, which bear a targeted modification of Lhx4 in the heterozygous state, are asymptomatic, whereas homozygous animals die shortly after birth. Nevertheless, we have isolated the human LHX4 gene, as well as the corresponding cDNA sequence, to test whether it could be involved in developmental defects of the human pituitary region. LHX4, which encodes a protein 99% identical to its murine counterpart, consists of six coding exons and spans >45 kb of the q25 region of chromosome 1. We report a family with an LHX4 germline splice-site mutation that results in a disease phenotype characterized by short stature and by pituitary and hindbrain (i.e., cerebellar) defects in combination with abnormalities of the sella turcica of the central skull base. This intronic mutation, which segregates in a dominant and fully penetrant manner over three generations, abolishes normal LHX4 splicing and activates two exonic cryptic splice sites, thereby predicting two different proteins deleted in their homeodomain sequence. These findings, which elucidate the molecular basis of a complex Mendelian disorder, reveal the fundamental pleiotropic role played by a single factor that tightly coordinates brain development and skull shaping during head morphogenesis.
Assuntos
Processamento Alternativo/genética , Nanismo/genética , Mutação em Linhagem Germinativa/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 1/genética , Clonagem Molecular , Análise Mutacional de DNA , Nanismo/fisiopatologia , Éxons/genética , Feminino , Genes Dominantes/genética , Humanos , Íntrons/genética , Proteínas com Homeodomínio LIM , Masculino , Dados de Sequência Molecular , Linhagem , Penetrância , Mapeamento Físico do Cromossomo , Hipófise/anormalidades , Sítios de Splice de RNA/genética , RNA Mensageiro/análise , RNA Mensageiro/genética , Rombencéfalo/anormalidades , Alinhamento de Sequência , Crânio/anormalidadesRESUMO
Type I oculocutaneous albinism (OCA) is an autosomal recessive disorder caused by the reduction or the absence of tyrosinase (TYR) activity in melanocytes of the skin, hair and eyes. Here we report an analysis of 45 patients with OCA. We found five novel mutations in the tyrosinase gene involved in the pathogenesis of oculocutaneous albinism type IA or type IB (OCA-1A/B) in five unrelated patients. Three mutations are missense mutations (G109R, P205T and H256Y) and two are nucleotide deletions (336-337delCA and 678-680delAGG). One patient is homozygous for the previously known V275F mutation but has an extremely mild OCA phenotype and has no eye features typical of OCA. In several patients we discovered only one or even no mutation in the coding sequence of the TYR gene. Thus, this disease may also result from mutations in non coding regions of the gene or in another gene involved in the biosynthesis of melanin. Hum Mutat 17:352, 2001.
