RESUMEN
Proteins of the bone morphogenetic protein (BMP) family are known to have a role in ocular and skeletal development; however, because of their widespread expression and functional redundancy, less progress has been made identifying the roles of individual BMPs in human disease. We identified seven heterozygous mutations in growth differentiation factor 6 (GDF6), a member of the BMP family, in patients with both ocular and vertebral anomalies, characterized their effects with a SOX9-reporter assay and western analysis, and demonstrated comparable phenotypes in model organisms with reduced Gdf6 function. We observed a spectrum of ocular and skeletal anomalies in morphant zebrafish, the latter encompassing defective tail formation and altered expression of somite markers noggin1 and noggin2. Gdf6(+/-) mice exhibited variable ocular phenotypes compatible with phenotypes observed in patients and zebrafish. Key differences evident between patients and animal models included pleiotropic effects, variable expressivity and incomplete penetrance. These data establish the important role of this determinant in ocular and vertebral development, demonstrate the complex genetic inheritance of these phenotypes, and further understanding of BMP function and its contributions to human disease.
Asunto(s)
Anomalías Múltiples/genética , Anomalías Múltiples/patología , Factor 6 de Diferenciación de Crecimiento/genética , Penetrancia , Secuencia de Aminoácidos , Animales , Análisis Mutacional de ADN , Genes Reporteros , Factor 6 de Diferenciación de Crecimiento/química , Humanos , Ratones , Modelos Animales , Datos de Secuencia Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Mutación/genética , Oligonucleótidos Antisentido/farmacología , Pez Cebra , Proteínas de Pez Cebra/química , Proteínas de Pez Cebra/genéticaRESUMEN
SOX6, a member of the SOX gene family, plays a key role in the development of several mammalian tissues and organs, including the central nervous system. Specifically, this gene modulates the differentiation and proliferation of interneurons in the medial ganglionic eminence, as well as oligodendrocytes in the spinal cord. We describe the case of a 4-year-old girl with global developmental delay and a spinal cord syrinx who presented with recurrent episodes of parkinsonian symptoms subsequent to febrile illnesses. The symptoms included gait instability, tremor, and dysarthria, with a progressive relapsing-remitting course over the span of 2 years. The patient was later found to have a large deletion-type mutation in the SOX6 gene. This case is the first report in humans implying a role for SOX6 in basal ganglia function, as well as spinal cord development.
Asunto(s)
Quistes/fisiopatología , Discapacidades del Desarrollo/fisiopatología , Trastornos Parkinsonianos/fisiopatología , Factores de Transcripción SOXD/genética , Eliminación de Secuencia , Siringomielia/genética , Preescolar , Quistes/genética , Quistes/patología , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Femenino , Humanos , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , Médula Espinal/patología , Siringomielia/patología , Siringomielia/fisiopatología , Vértebras TorácicasRESUMEN
PURPOSE: Anophthalmia is a heterogeneous developmental disorder characterized by absent eyes whose diverse etiology encompasses chromosomal and monogenic aberrations, as well as environmental causes. Since the molecular basis has been defined in only a small proportion of cases and extending this offers potential to enhance understanding of key steps in ocular development, a consanguineous anophthalmic pedigree was investigated using homozygosity mapping. METHODS: DNA samples from six individuals, two anophthalmic, were genotyped with an array featuring approximately 620,000 single nucleotide polymorphisms (SNPs) in order to identify homozygous or copy number variant (CNV) regions. Candidate genes located in regions of identity by descent (IBD) defined by homozygosity mapping were subsequently screened by direct sequencing. RESULTS: Genotyping identified five homozygous intervals (4q26-28.1, 13q12.11, 14q22.1-22.2, 15q26.2-26.3 and 19q13.12) larger than 1 Mb that do not correspond with the known loci and which contain a total of 205 annotated genes. No CNVs were identified that segregated with the disease phenotype, and sequencing of five candidate genes (PRDM5, FGF2, SOS2, POU2F2 and CIC) did not identify any mutations. CONCLUSIONS: Although constrained by the pedigree's size, the homozygosity mapping approach employed in this study extends the locus heterogeneity of anophthalmia. The results indicate that a novel molecular cause remains to be determined in this pedigree with the causative gene likely located within one of the five IBD regions.
Asunto(s)
Anoftalmos/genética , Heterogeneidad Genética , Ligamiento Genético , Niño , Femenino , Perfilación de la Expresión Génica , Genotipo , Técnicas de Genotipaje , Edad Gestacional , Homocigoto , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Polimorfismo de Nucleótido Simple , Agudeza VisualRESUMEN
22q11.2 microduplications of a 3-Mb region surrounded by low-copy repeats should be, theoretically, as frequent as the deletions of this region; however, few microduplications have been reported. We show that the phenotype of these patients with microduplications is extremely diverse, ranging from normal to behavioral abnormalities to multiple defects, only some of which are reminiscent of the 22q11.2 deletion syndrome. This diversity will make ascertainment difficult and will necessitate a rapid-screening method. We demonstrate the utility of four different screening methods. Although all the screening techniques give unique information, the efficiency of real-time polymerase chain reaction allowed the discovery of two 22q11.2 microduplications in a series of 275 females who tested negative for fragile X syndrome, thus widening the phenotypic diversity. Ascertainment of the fragile X-negative cohort was twice that of the cohort screened for the 22q11.2 deletion. We also report the first patient with a 22q11.2 triplication and show that this patient's mother carries a 22q11.2 microduplication. We strongly recommend that other family members of patients with 22q11.2 microduplications also be tested, since we found several phenotypically normal parents who were carriers of the chromosomal abnormality.