Characterization of survival motor neuron (SMNT) gene deletions in asymptomatic carriers of spinal muscular atrophy.
ABSTRACT Previous reports have established that the telomeric copy of the survival motor neuron (SMNT) gene and the intact copy of the neuronal apoptosis inhibitory protein (NAIP) gene are preferentially deleted in patients with spinal muscular atrophy (SMA). Although deletions or mutations in the SMNT gene are most highly correlated with SMA, it is not clear to what extent NAIP or other genes influence the SMA phenotype, or whether a small fraction of SMA patients actually have functional copies of both SMNT and NAIP. To evaluate further the part of SMNT in the development of SMA, we analyzed 280 asymptomatic SMA family members for the presence or absence of SMNT exons 7 and 8. We report the following observations: (i) 4% of the sample harbored a polymorphic variant of SMNT exon 7 that looks like a homozygous deletion; (ii) approximately 1% of the parents are homozygously deleted for both exons 7 and 8; (iii) one asymptomatic parent lacking both copies of SMNT exons 7 and 8 displays a 'subclinical phenotype' characterized by mild neurogenic pathology; (iv) another asymptomatic parent lacking both SMNT exons showed no signs of motor neuron disorder by clinical and neurodiagnostic analyses. The demonstration of polymorphic variants of exon 7 that masquerade as homozygous nulls, and the identification of SMA parents who harbor two disease alleles, serve as a caution to those conducting prenatal tests with these markers.
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ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive (AR) neuromuscular disease that is one of the most common lethal genetic disorders in children, with carrier frequencies as high as ∼1 in 35 in US Whites. As part of our genetic studies in the Hutterites from South Dakota, we identified a large 22 Mb run of homozygosity, spanning the SMA locus in an affected child, of which 10 Mb was also homozygous in three affected Hutterites from Montana, supporting a single founder origin for the mutation. We developed a haplotype-based method for identifying carriers of the SMN1 deletion that leveraged existing genome-wide SNP genotype data for ∼1400 Hutterites. In combination with two direct PCR-based assays, we identified 176 carriers of the SMN1 deletion, one asymptomatic homozygous adult and three carriers of a de novo deletion. This corresponds to a carrier frequency of one in eight (12.5%) in the South Dakota Hutterites, representing the highest carrier frequency reported to date for SMA and for an AR disease in the Hutterite population. Lastly, we show that 26 SNPs can be used to predict SMA carrier status in the Hutterites, with 99.86% specificity and 99.71% sensitivity.European journal of human genetics: EJHG 05/2011; 19(10):1045-51. · 3.56 Impact Factor
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ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of the survival motor neuron-1 (SMN1) gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, the SMN-encoded protein, SMN is the most important therapeutic target for development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy.Neural Plasticity 01/2012; 2012:456478. · 2.86 Impact Factor
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ABSTRACT: A number of neurological and muscular disorders are characterized by the accumulation of aggregate-prone proteins and are referred to as protein deposit or protein conformation diseases. Besides some sporadic forms, most of them are genetically inherited in an autosomal dominant manner, although recessive forms also exist. Although genetically very heterogeneous, some of these diseases are the result of mutations in some members of the mammalian small heat shock protein family (sHSP/HSPB), which are key players of the protein quality control system and participate, together with other molecular chaperones and co-chaperones, in the maintenance of protein homeostasis. Thus, on one hand upregulation of specific members of the HSPB family can exert protective effects in protein deposit diseases, such as the polyglutamine diseases. On the other hand, mutations in the HSPBs lead to neurological and muscular disorders, which may be due to a loss-of-function in protein quality control and/or to a gain-of-toxic function, resulting from the aggregation-proneness of the mutants. In this review we summarize the current knowledge about some of the best characterized functions of the HSPBs (e.g. role in cytoskeleton stabilization, chaperone function, anti-aggregation and anti-apoptotic activities), also highlighting differences in the properties of the various HSPBs and how these may counteract protein aggregation diseases. We also describe the mutations in the various HSPBs associated with neurological and muscular disorders and we discuss how gain-of-toxic function mechanisms (e.g. due to the mutated HSPB protein instability and aggregation) and/or loss-of-function mechanisms can contribute to HSPB-associated pathologies. This article is part of a Directed Issue entitled: Small HSPs in physiology and pathology.The international journal of biochemistry & cell biology 03/2012; 44(10):1657-69. · 4.89 Impact Factor