RESUMO
X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.
Assuntos
Variação Genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Animais , Células Cultivadas , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Estudos de Coortes , Quinases Ciclina-Dependentes/genética , Sequenciamento de Nucleotídeos em Larga Escala , Histona Acetiltransferases/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Neurônios/metabolismo , Neurônios/patologia , Proteínas Nucleares/genética , RNA Mensageiro/metabolismo , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Mutations in the brain specific P/Q type Ca2+ channel alpha1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, viz. episodic ataxia type 2 (EA-2), familial hemiplegic migraine (FHM) and spinocerebellar ataxia 6 (SCA6). For individuals with EA-2, the mutations described thus far are presumed to result in a truncated protein product. Several different missense mutations have been identified in patients with FHM. At least two of these mutations have been identified on two different chromosome 19p13 haplotypes and thus represent recurrent mutations. In the present study, we have screened several individuals for mutations in all 47 exons in the CACNA1A gene by single-strand conformation analysis. We have characterised a novel missense mutation, G5260A, in exon 32 in a family segregating for EA-2. The consequence of this mutation is an amino acid substitution at a highly conserved position within the CACNA1A gene. This represents the first point mutation not resulting in a proposed truncated protein. Furthermore, this mutation has been detected in a family member with mild clinical signs including only migraine. Additionally, a second previously identified recurrent muta tion, C2272T, in exon 16 has been discovered in a patient with FHM.
Assuntos
Ataxia/genética , Canais de Cálcio/genética , Hemiplegia/genética , Transtornos de Enxaqueca/genética , Sequência de Aminoácidos , Cromossomos Humanos Par 19/genética , DNA/química , DNA/genética , Análise Mutacional de DNA , Saúde da Família , Feminino , Ligação Genética , Hemiplegia/complicações , Humanos , Masculino , Repetições de Microssatélites , Transtornos de Enxaqueca/complicações , Dados de Sequência Molecular , Mutação , Mutação de Sentido Incorreto , Linhagem , Polimorfismo Conformacional de Fita Simples , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
In a large kindred in which the gene for central core disease is segregating, we have demonstrated linkage between the disorder and a marker on chromosome 19q. Marker D19S9 (p1J2) was linked to central core disease with a lod score of 6.4 at theta = 0.03 (support interval 0.01-0.14) thus localizing the gene for this disorder in or very close to 19q12-q13.2.
