RESUMEN
BACKGROUND: Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis. METHODS: In order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed. RESULTS: We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy. CONCLUSION: The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.
Asunto(s)
Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Malformaciones del Sistema Nervioso/genética , Polimicrogiria/genética , Tubulina (Proteína)/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Vermis Cerebeloso/diagnóstico por imagen , Vermis Cerebeloso/patología , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/patología , Masculino , Mutación Missense/genética , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Malformaciones del Sistema Nervioso/patología , Neuroimagen/métodos , Fenotipo , Polimicrogiria/diagnóstico por imagen , Polimicrogiria/patología , Tubulina (Proteína)/deficiencia , Adulto JovenRESUMEN
PURPOSE: The Israeli and Palestinian populations are known to have a relatively high level of consanguineous marriages, leading to a relatively high frequency of autosomal recessive (AR) diseases. Our purpose was to use the homozygosity mapping approach, aiming to prioritize the set of genes and identify the molecular genetic causes underlying AR retinal degenerations in the Israeli and Palestinian populations. METHODS: Clinical analysis included family history, ocular examination, full-field electroretinography (ERG), and funduscopy. Molecular analysis included homozygosity mapping and mutation analysis of candidate genes. RESULTS: We recruited for the study families with AR nonsyndromic retinal degenerations, including mainly retinitis pigmentosa (RP), cone-rod degeneration (CRD), and Leber congenital amaurosis (LCA). With the aim to identify the causative genes in these families, we performed homozygosity mapping using whole genome single nucleotide polymorphism (SNP) arrays in 125 families. The analysis revealed the identification of 14 mutations, 5 of which are novel, in 16 of the families. The mutations were identified in the following eight genes: RDH12, PROM1, MFRP, TULP1, LCA5, CEP290, NR2E3, and EYS. While most patients had a retinal disease that is compatible with the causing gene, in some cases new clinical features are evident. CONCLUSIONS: Homozygosity mapping is a powerful tool to identify genetic defects underlying heterogeneous AR disorders, such as RP and LCA, in consanguineous and nonconsanguineous patients. The identification of significant and large homozygous regions, which do not include any known retinal disease genes, may be a useful tool to identify novel disease-causing genes, using next generation sequencing.
Asunto(s)
Análisis Mutacional de ADN , Proteínas del Ojo/genética , Predisposición Genética a la Enfermedad , Mutación , Polimorfismo de Nucleótido Simple , Degeneración Retiniana/genética , Retinitis Pigmentosa/genética , Árabes/etnología , Mapeo Cromosómico , Consanguinidad , Electrorretinografía , Femenino , Ligamiento Genético , Homocigoto , Humanos , Israel/epidemiología , Judíos/etnología , Masculino , Linaje , Degeneración Retiniana/etnología , Retinitis Pigmentosa/etnologíaRESUMEN
Integrin-associated protein (IAP) is a widely expressed membrane protein with multiple functions in immunological and neuronal processes. Having physically mapped the IAP gene into a BAC/PAC contig covering approximately 1 Mb on human chromosome 3ql3.1-q13.2, we determined the genomic organization of the gene, established its expression in skeletal muscle, and identified a novel splice variant. Our expression studies demonstrate expression of integrin-associated protein in the t-tubular system and the euchromatin of skeletal muscle cells where its function thus far is not known.