Screening of deletions in SMN, NAIP and BTF2p44 genes in Turkish spinal muscular atrophy patients

Deletions of the spinal muscular atrophy (SMA)-determining gene, SMN1, NAIP, and a third multicopy gene, BTF2p44tel were investigated in 60 unrelated Turkish SMA patients. SMN1 was deleted for at least exons 7 and 8 in 85% of the Turkish SMA patients. The NAIP gene was deleted in 75 and 33% of type I and type II SMA patients, respectively. Analysis of the 5'end of the BTF2p44tel gene indicated the extension of deletion in 13.3% of the cases, mainly in type I patients. Deletions of the NAIP and BTF2p44tel genes were detected in 1.3 and 3.9% of carrriers, respectively, in Turkish SMA families. Two patients were detected to harbor the hybrid SMN gene, one type II with deletion of the NAIP gene, and one type III without deletion of the NAIP gene.     

DNA analysis in Turkish Duchenne/Becker muscular dystrophy families

Summary The molecular genetics of Duchenne/Becker muscular dystrophy was investigated in 81 affected Turkish families. Deletions were detected by multiplex polymerase chain reaction assays and cDNA Southern analyses. The distribution of the deletions along the gene and their correlation to clinical phenotype were different from the studies reported on other populations. Moreover, DNA polymorphisms in mothers were determined using 8 DNA probes and three CA repeat sequences, and a high degree of informativeness was observed.     

Haploinsufficiency of TBX3 causes ulnar-mammary syndrome in a large Turkish family

We present a large Turkish family with autosomal dominant inherited ulnar-mammary syndrome in which 10 affected family members, spanning three generations, were diagnosed. The phenotypic expression of the disease was found to be highly variable among the affected family members showing posterior-limb deficiencies and/or duplications, mammary-gland hypoplasia, apocrine dysfunction, dental and genital abnormalities. Mutation analysis of the TBX3 gene showed a novel one base-pair insertion at position 89 (designated 88_89insA) in the coding region. The mutation leads to a shift of the open reading frame and causes a premature truncation of the protein (M30fsX110). The truncated protein lacks almost all functional important parts of TBX3, most likely leading to a complete loss of functional protein. Our findings indicate that ulnar-mammary syndrome shows a wide range of phenotypes even within the same family and provide further evidence that haploinsufficiency of TBX3 is the disease-causing mechanism.     

Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive syndromes of unknown etiology characterized by multiple, recurring subcutaneous tumors, gingival hypertrophy, joint contractures, osteolysis, and osteoporosis. Both are believed to be allelic disorders; ISH is distinguished from JHF by its more severe phenotype, which includes hyaline deposits in multiple organs, recurrent infections, and death within the first 2 years of life. Using the previously reported chromosome 4q21 JHF disease locus as a guide for candidate-gene identification, we identified and characterized JHF and ISH disease-causing mutations in the capillary morphogenesis factor-2 gene (CMG2). Although CMG2 encodes a protein upregulated in endothelial cells during capillary formation and was recently shown to function as an anthrax-toxin receptor, its physiologic role is unclear. Two ISH family-specific truncating mutations, E220X and the 1-bp insertion P357insC that results in translation of an out-of-frame stop codon, were generated by site-directed mutagenesis and were shown to delete the CMG-2 transmembrane and/or cytosolic domains, respectively. An ISH compound mutation, I189T, is predicted to create a novel and destabilizing internal cavity within the protein. The JHF family-specific homoallelic missense mutation G105D destabilizes a von Willebrand factor A extracellular domain alpha-helix, whereas the other mutation, L329R, occurs within the transmembrane domain of the protein. Finally, and possibly providing insight into the pathophysiology of these diseases, analysis of fibroblasts derived from patients with JHF or ISH suggests that CMG2 mutations abrogate normal cell interactions with the extracellular matrix.