ABSTRACT
Marshall-Smith syndrome (MSS) is a very rare malformation syndrome characterized by typical craniofacial anomalies, abnormal osseous maturation, developmental delay, failure to thrive, and respiratory difficulties. Mutations in the nuclear factor 1/X gene (NFIX) were recently identified as the cause of MSS. In our study cohort of 17 patients with a clinical diagnosis of MSS, conventional sequencing of NFIX revealed frameshift and splice-site mutations in 10 individuals. Using multiplex ligation-dependent probe amplification analysis, we identified a recurrent deletion of NFIX exon 6 and 7 in five individuals. We demonstrate this recurrent deletion is the product of a recombination between AluY elements located in intron 5 and 7. Two other patients had smaller deletions affecting exon 6. These findings show that MSS is a genetically homogeneous Mendelian disorder. RT-PCR experiments with newly identified NFIX mutations including the recurrent exon 6 and 7 deletion confirmed previous findings indicating that MSS-associated mutant mRNAs are not cleared by nonsense-mediated mRNA decay. Predicted MSS-associated mutant NFIX proteins consistently have a preserved DNA binding and dimerization domain, whereas they grossly vary in their C-terminal portion. This is in line with the hypothesis that MSS-associated mutations encode dysfunctional proteins that act in a dominant negative manner.
Subject(s)
Abnormalities, Multiple/genetics , Alu Elements , Bone Diseases, Developmental/genetics , Craniofacial Abnormalities/genetics , Exons , NFI Transcription Factors/genetics , Septo-Optic Dysplasia/genetics , Sequence Deletion , Abnormalities, Multiple/diagnosis , Adolescent , Adult , Bone Diseases, Developmental/diagnosis , Child , Child, Preschool , Chromosome Breakpoints , Craniofacial Abnormalities/diagnosis , DNA Mutational Analysis , Facies , Female , Gene Expression , Genetic Loci , Humans , Infant , Male , Mutation , Phenotype , RNA, Messenger/genetics , Septo-Optic Dysplasia/diagnosis , Young AdultABSTRACT
Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome. Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish. Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans.
