ABSTRACT
The past few years have seen rapid advances in our understanding of the genetics and molecular biology of cerebral cavernous malformations (CCM) with the identification of the CCM1, CCM2, and CCM3 genes. Recently, we have recruited a patient with an X/3 balanced translocation that exhibits CCM. By fluorescent in situ hybridization analysis, sequence analysis tools and database mining procedures, we refined the critical region to an interval of 200-kb and identified the interrupted ZPLD1 gene. We detected that the mRNA expression level of ZPLD1 gene is consistently decreased 2.5-fold versus control (P=0.0006) with allelic loss of gene expression suggesting that this protein may be part of the complex signaling pathway implicated in CCM formation.
Subject(s)
Chromosomes, Human, Pair 3 , Hemangioma, Cavernous, Central Nervous System/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , Signal Transduction/physiology , Translocation, Genetic , Adult , Cell Line , Chromosome Breakage , Databases, Protein , Female , Hemangioma, Cavernous, Central Nervous System/metabolism , Hemangioma, Cavernous, Central Nervous System/pathology , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/physiology , Magnetic Resonance Imaging , Phenotype , Primary Ovarian Insufficiency/complications , Primary Ovarian Insufficiency/genetics , RNA, Messenger/metabolism , X Chromosome Inactivation/geneticsABSTRACT
Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19q13 (DM1) or 3q21 (DM2/PROMM). DM1 is caused by a CTG expansion in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). Several mechanisms have been invoked to explain how this mutation, which does not alter the protein-coding portion of a gene, causes the specific constellation of clinical features characteristic of DM. We now report that DM2 is caused by a CCTG expansion (mean approximately 5000 repeats) located in intron 1 of the zinc finger protein 9 (ZNF9) gene. Parallels between these mutations indicate that microsatellite expansions in RNA can be pathogenic and cause the multisystemic features of DM1 and DM2.
