Which is the genetic basis of Spinal Muscular Atrophy (SMA)?
['Mutations in TRPV4, encoding a cation channel, have recently been identified in one large dominant congenital spinal muscular atrophy kindred, but the genetic basis of dominant congenital spinal muscular atrophy in many families remains unknown.', 'We report clinical, electrophysiology, muscle magnetic resonance imaging and histopathology findings in a four generation family with typical dominant congenital spinal muscular atrophy features, without mutations in TRPV4, and in whom linkage to other known dominant neuropathy and spinal muscular atrophy genes has been excluded. The autopsy findings in the proband, who died at 14 months of age from an unrelated illness, provided a rare opportunity to study the neuropathological basis of dominant congenital spinal muscular atrophy. There was a redu', 'Recently, the common forms of spinal muscular atrophy (SMA) have been associated with mutations of the SMN and NAIP genes on chromosome 5, in the region q11.2-13.3.', 'Some correlation has been established between SMN protein levels and disease course; nevertheless, the genetic basis for SMA phenotypic variability remains unclear, and it has been postulated that the loss of an additional modifying factor contributes to the severity of type I SMA', 'Using comparative genomics to screen for such a factor among evolutionarily conserved sequences between mouse and human, we have identified a novel transcript, H4F5, which lies closer to SMN1 than any previously identified gene in the region.', 'A multi-copy microsatellite marker that is deleted in more than 90% of type I SMA chromosomes is embedded in an intron of this gene, indicating that H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.', 'A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy', 'A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA).', 'Thus, the failure of SMN2 to fully compensate for SMN1 and protect from SMA is due to a nucleotide exchange (C/T) that attenuates activity of an exonic enhancer.', 'Autosomal recessive childhood proximal SMA is the commonest form and is due to mutations in a gene encoding a novel protein, SMN, that appears to play a critical role in RNA metabolism but has also been shown to interact with actin-binding proteins and mediators of programmed cell death.', 'Mutations of the SMN1 gene are responsible for SMA.', 'All patients were found to be homozygous for the loss of either exon 7 or exons 7 and 8 of the SMN1 gene', 'Six additional patients had anterior horn cell disease but were negative for the SMN1 gene deletion. All six had exclusion features listed in the international guidelines.', 'The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1)', 'The structures of the SMN1 gene and SMN2 pseudogene, mutations distorting the SMN1 function, the structure and functions of the Smn neurotrophic protein, its role in biogenesis of small nuclear ribonucleoproteins (snRNPs), and the principles and prdblems of molecular diagnosis in SMA are described.', 'SMA are caused by mutations of the survival of motor neuron gene (SMN1) leading to a reduction of the SMN protein amount.', 'From a better knowledge of the genetic basis of SMA and the defects resulting from the mutations of SMN1 in cellular or animal models, several therapeutics strategies have been selected aiming at targeting SMN2, a partially functional copy of SMN1 gene which remains present in patients, or to prevent neurons from death.', 'We used a homozygosity mapping and positional cloning approach in a consanguineous family of Ashkenazi Jewish origin and identified a nonsense mutation in the vaccinia-related kinase 1 gene (VRK1) as a cause of SMA-PCH', 'SMN1 and SMN2 quantification was undertaken to investigate the genotype-phenotype relationship.RESULTS: Two novel point mutations were identified in exon 3 of SMN1 (p.Tyr130Cys and p.Tyr130His) in the highly conserved Tudor domain of the Smn protein.CONCLUSIONS: The genetic basis of SMA in the rare cases of compound heterozygous carriers of SMN1 deletions is complex. ']
['The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1). Mutations of the SMN1 gene are responsible for SMA. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. A critical question is why only the homozygous loss of SMN1, and not SMN2, results in spinal muscular atrophy (SMA). H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.\nThe molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1).']
['The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1)']