RESUMO
A partial deletion of chromosome band 2p25.3 (2pter) is a rarely described cytogenetic aberration in patients with intellectual disability (ID). Using microarrays we identified deletions of 2p25.3, sized 0.37-3.13 Mb, in three adult siblings and three unrelated patients. All patients had ID, obesity or overweight and/or a square-shaped stature without overt facial dysmorphic features. Combining our data with phenotypic and genotypic data of three patients from the literature we defined the minimal region of overlap which contained one gene, i.e., MYT1L. MYT1L is highly transcribed in the mouse embryonic brain where its expression is restricted to postmitotic differentiating neurons. In mouse-induced pluripotent stem cell (iPS) models, MYT1L is essential for inducing functional mature neurons. These resemble excitatory cortical neurons of the forebrain, suggesting a role for MYT1L in development of cognitive functions. Furthermore, MYT1L can directly convert human fibroblasts into functional neurons in conjunction with other transcription factors. MYT1L duplication was previously reported in schizophrenia, indicating that the gene is dosage-sensitive and that shared neurodevelopmental pathways may be affected in ID and schizophrenia. Finally, deletion of MYT1, another member of the Myelin Transcription Factor family involved in neurogenesis and highly similar to MYT1L, was recently described in ID as well. The identification of MYT1L as candidate gene for ID justifies further molecular studies aimed at detecting mutations and for mechanistic studies on its role in neuron development and on neuropathogenic effects of haploinsufficiency.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Cariótipo Anormal , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Cromossomos Humanos Par 2/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Haploinsuficiência , Humanos , Hibridização in Situ Fluorescente , Lactente , Deficiência Intelectual/metabolismo , Masculino , Metáfase , Pessoa de Meia-Idade , Neurogênese , Obesidade/genética , Análise de Sequência com Séries de Oligonucleotídeos , Sobrepeso/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/metabolismoRESUMO
A 55-year-old man sought care for aggressive acute lymphoblastic leukemia (ALL), which developed 8 years after he had received chemotherapeutic treatment for nephrotic syndrome. The sole cytogenetic abnormality observed in bone marrow-derived metaphases was a t(4;11)(q21;q23), which is a frequently occurring translocation in ALL. However, subsequent reverse transcriptase-polymerase chain reaction for the expected mixed lineage leukemia [trithorax homolog, Drosophila] (MLL)-AFF1 fusion transcript was negative. Further fluorescence in situ hybridization (FISH) analysis narrowed the 4q21 breakpoint down to a 250-kb region proximal of AFF1. This comprised four genes, of which septin11 (SEPT11) was further analyzed. Reverse transcriptase-polymerase chain reaction revealed expression of a chimeric MLL-SEPT11 transcript, thus identifying what is to our knowledge a hitherto undescribed translocation in ALL. Sequence analysis of cDNA showed in-frame fusion of MLL exon 11 to SEPT11 exon 2. This MLL-SEPT11 fusion is cytogenetically indistinguishable from the recurrent t(4;11)(q21;q23). Thus, it is crucial to characterize cytogenetic aberrations in leukemia by molecular methods, even in cases where a known recurrent translocation is presumed. This report expands the spectrum of ALL-related translocations and hypothesizes on the mechanism leading to the MLL-SEPT11 fusion. Five septins have been identified thus far as MLL fusion partners in leukemia. Their putative oncogenic role may be related to forced MLL dimerization by the septin coiled coil and GTP-binding domains, which could convert MLL to an oncogene.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Fusão Gênica , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas Nucleares/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Sequência de Bases , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 4 , Primers do DNA , Histona-Lisina N-Metiltransferase , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Septinas , Fatores de Elongação da TranscriçãoRESUMO
The degenerate subcutaneous eye of the blind mole rat belonging to the Spalax ehrenbergi superspecies has been shown to contain a long wavelength sensitive (LWS) cone pigment. Baculovirus expression of this LWS pigment and subsequent IMAC purification yields a photosensitive protein, that according to absorbance maximum (530 +/- 2 nm), kinetics of late phototransitions, and transducin activation, has all characteristics of a functional green cone pigment. The absorbance spectrum of the Spalax pigment is strongly red-shifted relative to the very homologous mouse, rabbit and rat green cone pigments (508-510 nm). Also in contrast to the rodent pigments, the Spalax pigment exhibits anion-dependent spectral properties, displaying a 12 nm blue-shift upon substitution of chloride ions by nitrate ions. Finally, the slow part of the photocascade deviates in some aspects from that of sighted mammals. The possible relevance of these findings for the evolutionary adaptation of Spalax to a subterranean ecotope is discussed.