ABSTRACT
The authors describe a family with six patients with muscular dystrophy with a variable course. One is a compound heterozygote for CAPN3 mutations (calpainopathy) and the others have a single CAPN3 mutation. Linkage analysis and sequencing revealed a XK gene mutation (McLeod syndrome). This illustrates the variable phenotype of XK mutations and suggests the possibility that CAPN3 heterozygotes may have their condition caused by nonallelic mutations in other unrelated genes.
Subject(s)
Calpain/genetics , Chorea/genetics , Genetic Diseases, X-Linked/genetics , Genetic Predisposition to Disease/genetics , Isoenzymes/genetics , Muscle Proteins/genetics , Muscular Dystrophies, Limb-Girdle/genetics , Mutation/genetics , Adolescent , Adult , Amino Acid Transport Systems, Neutral/genetics , Chorea/complications , Chorea/physiopathology , Chromosome Mapping , Codon, Nonsense/genetics , DNA Mutational Analysis , Genetic Diseases, X-Linked/complications , Genetic Diseases, X-Linked/physiopathology , Genetic Testing , Genotype , Humans , Male , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Muscular Dystrophies, Limb-Girdle/complications , Muscular Dystrophies, Limb-Girdle/physiopathology , Pedigree , Phenotype , SyndromeABSTRACT
Recently, a novel exon was described in TCOF1 that, although alternatively spliced, is included in the major protein isoform. In addition, most published mutations in this gene do not conform to current mutation nomenclature guidelines. Given these observations, we developed an online database of TCOF1 mutations in which all the reported mutations are renamed according to standard recommendations and in reference to the genomic and novel cDNA reference sequences (www.genoma.ib.usp.br/TCOF1_database). We also report in this work: 1) results of the first screening for large deletions in TCOF1 by Southern blot in patients without mutation detected by direct sequencing; 2) the identification of the first pathogenic mutation in the newly described exon 6A; and 3) statistical analysis of pathogenic mutations and polymorphism distribution throughout the gene.
Subject(s)
Alternative Splicing , Databases, Nucleic Acid , Exons/genetics , Mandibulofacial Dysostosis/genetics , Mutation , Nuclear Proteins/genetics , Phosphoproteins/genetics , Terminology as Topic , Base Sequence , Humans , Molecular Sequence Data , Mutation, MissenseABSTRACT
Knobloch syndrome is an autosomal recessive disease characterized by the early onset of severe myopia, vitreoretinal degeneration with retinal detachment, macular abnormalities, and midline encephalocele, mainly in the occipital region. Intra and interfamilial variability is present since the encephalocele is not found in all patients, and the degree of myopia is variable. Analysis of the associated malformations suggests alterations during early neuroectodermal morphogenesis. Only 24 cases have been reported. Recently, the gene responsible for the syndrome, mapped to 21q22.3, was identified. The present study reports on four new cases, revealing the existence of neuronal migratory defects associated with the disorder for the first time.
