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PubMed2004

In vivo selection reveals combinatorial controls that define a critical exon in the spinal muscular atrophy genes.

Humans have two near identical copies of the survival of motor neuron (SMN) gene, SMN1 and SMN2. In spinal muscular atrophy (SMA), SMN2 is not able to compensate for the loss of SMN1 due to an inhibitory mutation at position 6 (C6U mutation in transcript) of exon 7. We have recently shown that C6U creates an extended inhibitory context (Exinct) that causes skipping of exon 7 in SMN2. Previous studies have shown that an exonic splicing enhancer associated with Tra2 (Tra2-ESE) is required for exon 7 inclusion in both SMN1 and SMN2. Here we describe the method of in vivo selection that determined the position-specific role of wild-type nucleotides within the entire exon 7. Our results confirmed the existence of Exinct and revealed the presence of an additional inhibitory tract (3'-Cluster) near the 3'-end of exon 7. We also demonstrate that a single nucleotide substitution at the last position of exon 7 improves the 5' splice site (ss) such that the presence of inhibitory elements (Exinct as well as the 3'-Cluster) and the absence of Tra2-ESE no longer determined exon 7 usage. Our results suggest that the evolutionary conserved weak 5' ss may serve as a mechanism to regulate exon 7 splicing under different physiological contexts. This is the first report in which a functional selection method has been applied to analyze the entire exon. This method offers unparallel advantage for determining the relative strength of splice sites, as well as for identifying the novel exonic cis-elements.

Base Sequence↗
PubMed2004

Joint range of motion limitations in children and young adults with spinal muscular atrophy.

OBJECTIVES: To elicit descriptive data about limited joint range of motion (ROM) in subjects with type II or III spinal muscular atrophy (SMA) and to examine the relation between the number of motions with limited range and both age and functional ability. DESIGN: Descriptive cross-sectional study. SETTING: Neurologic pediatric outpatient clinic at a hospital in Taiwan. PARTICIPANTS: Twenty-seven subjects with SMA type II (mean age, 9.8+/-6.5y) and 17 with SMA type III (mean age, 12.2+/-8.7y). Intervention Measurement with transparent goniometers of joint ROM bilaterally of the shoulder, elbow, wrist, hip, knee, and ankle. MAIN OUTCOME MEASURES: The proportion of participants with each ROM limitation compared with all participants with the same SMA type, age distribution of the participants with each ROM limitation, mean range loss of each motion limitation, and the contracture index (risk index of joint contracture). RESULTS: Eighty-nine percent of the participants with SMA type II experienced knee extension limitation. Approximately 50% of the participants with both types of SMA had ankle dorsiflexion limitation. The motions of knee and hip extension and ankle dorsiflexion also had a relatively high contracture index. The number of motions with limited range positively correlated ( P <.001) with age and upper-extremity functional grade (the higher the functional grade, the poorer the functional ability) for SMA type II. CONCLUSIONS: We found varying degrees of joint ROM limitation. Certain motions were noted to be high risks for the development of contractures. This risk was higher mostly in younger children.

Adolescent↗
PubMed1998

Spinal muscular atrophy due to an isolated deletion of exon 8 of the telomeric survival motor neuron gene.

Patients with autosomal recessive spinal muscular atrophy (SMA) usually carry a homozygous deletion of exons 7 and 8 of the telomeric survival motor neuron (SMN(T)) gene, although an isolated deletion of SMN(T) exon 8 has never been found. We now report on 2 patients with the typical features of SMA types II and III, who carried a homozygous deletion of SMN(T) exon 8 but retained SMN(T) exon 7. Importantly, to exclude a sequence conversion event of telomeric exon 8, we amplified a fragment that spanned exons 7 and 8 of the SMN gene. The resulting 1,010-base pair (bp) fragments were subjected to nested polymerase chain reaction (PCR) of exon 7. The subsequent restriction analysis failed to show any products of telomeric exon 7, as the site for primer 541C1120 was lost in both alleles. These findings indicate a homozygous deletion of SMN(T) exon 8. Direct sequencing of the cloned 1,010-bp fragment further confirmed that these 2 SMA patients did not possess telomeric exon 8. The more severely affected child also showed a deletion of the neuronal apoptosis inhibitory protein (NAIP) gene. The present findings provide evidence that an isolated deletion of SMN(T) exon 8 is associated with the milder subtypes of SMA. Our data also demonstrate that the additional deletion of the NAIP gene exacerbates the severity of the disease.

Adult↗
PubMed1995

Prenatal prediction in families with autosomal recessive proximal spinal muscular atrophy (5q11.2-q13.3): molecular genetics and clinical experience in 109 cases.

Prenatal prediction in families at risk for autosomal recessive proximal spinal muscular atrophy (SMA) mainly of type I is often requested due to the high incidence and the fetal outcome of the disease. So far, only indirect genotype analysis can be performed in SMA families, since the gene has not yet been identified. We present our experience of 109 prenatal diagnoses obtained in 91 families by use of single- and multi-locus polymorphic microsatellites of the region 5q11.2-q13.3. The marker combinations and specific features of the closest microsatellites are described in detail. From 137 requests for prenatal prediction of SMA between October 1991 and August 1994, 28 families were excluded, mostly because the clinical diagnosis was uncertain or doubtful. Others had to be classified as 'SMA-variants' or showed autosomal dominant transmission of SMA. Of the 109 prenatal diagnoses performed, 29 fetuses were diagnosed to be at high risk (> 99 per cent) of developing the disease, while in seven additional pregnancies no exact prediction could be made due to a recombination event in one parental haplotype. Altogether, recombinations between closely flanking markers were observed in 14 cases. In 35 cases, the parents decided to terminate the pregnancy. Of the remaining pregnancies, 32 could be followed beyond term. All infants were reported to develop normally without signs of SMA. Two children were born with transverse reduction defects of one hand, which was most likely related to early chorionic villus sampling at 9 and 10 weeks' gestation. No further abnormalities could be detected. The limits of indirect genotype analysis and the problems of diagnostic accuracy and heterogeneity of proximal SMA are discussed.

Alleles↗
PubMed2001

Lung clearance in children with Duchenne muscular dystrophy or spinal muscular atrophy with and without CPAP (continuous positive airway pressure).

Bronchiolar clearance was studied in 7 boys in the age range of 8 to 17 years, 6 with Duchenne muscular dystrophy (DMD) and 1 with spinal muscular atrophy type II (SMA-II). These boys had healthy lungs but a severely reduced muscular strength (wheelchair dependent). In 6 of the boys, clearance was studied twice, at one occasion as a control and at the other occasion following treatment with continuous positive airway pressure (CPAP). A control group of healthy adults was used. In the clearance examinations, 6-microm Teflon particles, labeled with III In was inhaled extremely slowly, 0.05 L/s. This gives a deposition mainly in the bronchioles. Lung retention was measured after 0,24,48, and 72 hours. A model for deposition of particles in the adult lung was scaled down to represent the children in this study. Deposition in various airway generations was calculated to be similar in children and adults. Also the measured retentions were similar in the boys and the adults. In the clearance experiments during CPAP treatment, there was a significantly lower retention after 72 hours (but not after 24 and 48 hours) than in the control experiments. Theresults indicate that a severe reduction of muscular strength, and thereby a reduction of mechanical movement of the lung, does not affect clearance from large and small airways. However, some effect of clearance from small airways cannot be excluded due to the short measuring period. The small but significant effect of the CPAP treatment might have potential clinical importance and suggest that bronchiolar clearance can be affected by some form of mechanical force.

Adolescent↗
PubMed1986

[Association of a pediatric bullous eruption, cutaneous and muscular atrophy, hyperpigmentation and dysmorphism. A new entity?].

We report the case of a young patient who presented with dysmorphism, bullous eruption of childhood, cutaneous and muscular atrophy and hyperpigmentation. Attempts were made to find out where this case fits in the nosological framework. This young boy without any particular family history was born with facial dysmorphism consisting of micrognathia, right microphtalmos, gothic palate and left facial palsy of the peripheral type. At the age of 2 years and 9 months, generalized fragility of the skin appeared in the form of a recurrent bullous eruption. The bullae left numerous atrophic and depigmented scars; they spared the mucosae, and there was no photosensitivity. At the same time, generalized skin atrophy developed: the subcutaneous venous network was abnormally visible and there was diffuse hyperpigmentation. The hair was fine, curly and thin. The teeth dystrophic and abnormally positioned. The cornea of the right eye was invaded by conjunctiva. The bullous eruption subsided when the child was about 6 years' old, but the skin atrophy became worse and was accompanied with amyotrophy of the limbs and retraction in flexion of the joints at the extremities. Chronic ulcerations were present on the lower limbs. Statural and ponderal growth, as well as mental development were normal. The biochemical examinations performed revealed no abnormality. Light and electron microscopy of the skin showed a normal dermis-epidermis junction, but the anchorage fibres were rarefied. The dermal connective tissue was abnormal, with thin collagen fibres and disorganized fibrillae. Fibroblasts were hypoplastic and numerous. The elastic network was meagre and elastic fibres had a slashed appearance. Biopsy of a palmar nodule showed cheloid-like lesions. The nosological discussion involved some congenital bullous diseases and certain forms of connective tissue dystrophia. Among the bullous diseases, congenital poikiloderma, as described by Weary and Kindler, is unaccompanied with amyotrophy, articular retraction or dysmorphism. According to Verret et al., the bulla is located at the dermis-epidermis junction. Recessive dystrophic epidermolysis bullosa seems to differ from our case in that skin atrophy is localized and amyotrophy, dysmorphism and disorders of pigmentation are absent. In addition, we found no histological evidence of collagenolysis. Mendes Da Costa's bullous dystrophy can be excluded, as there was no nanism, microcephaly or diffuse alopecia in our patient. Among connective tissue dystrophias, acrogeria Ehlers-Danlos type IV syndrome does not include bullous eruption, amyotrophy or articular retraction.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormalities, Multiple↗
PubMed1993

Refined linkage map of chromosome 5 in the region of the spinal muscular atrophy gene.

The genetic map in the region of human chromosome 5 that harbors the gene for autosomal recessive forms of spinal muscular atrophy (SMA) has been refined by a multilocus linkage study in 50 SMA-segregating families. Among six markers spanning 8 cM for combined sexes, four were shown to be tightly linked to the SMA locus. Multipoint linkage analysis was used to establish the best estimate of the SMA gene location. Our data suggest that the most likely location for the SMA locus is between blocks AFM114ye7 (D5S465)/EF5.15 (D5S125) and MAP-1B/JK53 (D5S112) at a sex-combined genetic distance of 2.4 and 1.7 cM, respectively. Thus the SMA gene lies in the 4-cM region between these two blocks. This information is of primary importance for designing strategies for isolating the SMA gene.

Base Sequence↗
PubMed1998

Ribonucleoprotein assembly: clues from spinal muscular atrophy.

Mutation or deletion of one of the two genes encoding a protein known as SMN has recently been shown to cause spinal muscular atrophy. The SMN protein has been found to be part of a multi-component complex that appears to function in the assembly of cellular ribonucleoprotein particles.

Animals↗
PubMed1998

Molecular diagnosis of spinal muscular atrophy.

The frequency of deletions within the survival motor neurone (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes in patients with spinal muscular atrophy (SMA), and the impact of this on the diagnosis and prenatal diagnosis of SMA, were investigated by molecular analysis of stored DNA and retrospective review of case notes. In type I SMA, 16 of 17 cases were homozygously deleted for exons 7 and 8 of SMN, 14 of 17 were homozygously deleted for exon 5 of NAIP, and 13 of 17 were deleted for both. In types II and III SMA, seven of nine cases were deleted for exons 7 and 8 of SMN. Deletions of SMN and NAIP occurred in four of nine cases. With one exception, the deletion genotypes of probands, affected siblings, and terminated fetuses were identical. Molecular studies are replacing conventional investigations for SMA and have a high uptake prenatally.

Cyclic AMP Response Element-Binding Protein↗
PubMed1997

[The skin vasomotor dysfunction of the juvenile muscular atrophy of the distal upper limb--investigation by the ice water immersion test].

We investigated the skin vasomotor function of the juvenile muscular atrophy of the distal upper limb (JMA) by the ice water immersion test. The skin temperature of the bilateral second fingers during ice water immersion were measured in 17 patients with JMA and 25 normal controls. The insufficient fall of the skin temperature during ice water immersion was observed in 5 patients (3 patients in atrophic side, 2 patients in non-atrophic side). The insufficient recovery of the skin temperature was observed in 6 patients (3 patients in atrophic side, 3 patients in non-atrophic side). The both of the insufficient fall and recovery of the skin temperature was observed in one patient (both sides). The insufficient fall of the skin temperature indicates the hypofunction of skin vasomotor activity, and the insufficient recovery of the skin temperature indicates the hyperfunction of skin vasomotor activity because JMA has no disturbance of the peripheral sensory nerve fibers. We conclude that the responsible lesion of these abnormalities may be in the descending sympathetic tract in the cervical spinal cord.

Adolescent↗
PubMedDate not supplied

Assessment of nonallelic genetic heterogeneity of chronic (type II and III) spinal muscular atrophy.

We have previously reported the mapping of the chronic (type II/intermediate and type III/mild/Kugelberg-Welander) form of the childhood-onset spinal muscular atrophies (SMA) to chromosome 5q11.2-13.3, with evidence for nonallelic genetic heterogeneity within a small sample of seven families [Brzustowicz et al., Nature 1990;344:540-541]. We now report the results of linkage analysis and heterogeneity testing on a set of 38 families with chronic SMA. Significant evidence for nonallelic heterogeneity was detected among these families, with the predominant locus for chronic SMA mapping to a 0.51-cM region on 5q, between the loci D5S6 and MAP1B. The estimated proportion of linked families, alpha, was 0.91, with a 2.3-unit support interval of 0.75 to 0.98. The indication that some families diagnosed with chronic SMA are not linked to chromosome 5q must be considered in strategies to map the SMA locus. The relevance of these findings to acute SMA (SMA type I, severe, Werdnig-Hoffmann disease) is still unknown.

Adolescent↗
PubMed1995

Refined physical map of the spinal muscular atrophy gene (SMA) region at 5q13 based on YAC and cosmid contiguous arrays.

The gene for the autosomal recessive neurodegenerative disorder spinal muscular atrophy has been mapped to a region of 5q13 flanked proximally by CMS-1 and distally by D5S557. We present a 2-Mb yeast artificial chromosome (YAC) contig constructed from three libraries encompassing the D5S435/D5S629/CMS-1-SMA-D5S557/D5S112 interval. The D5S629/CMS-1-SMA-D5S557 interval is unusual insofar as chromosome 5-specific repetitive sequences are present and many of the simple tandem repeats (STR) are located at multiple loci that are unstable in our YAC clones. A long-range restriction map that demonstrates the SMA-containing interval to be 550 kb is presented. Moreover, a 210-kb cosmid array from both a YAC-specific and a chromosome 5-specific cosmid library encompassing the multilocus STRs CATT-1, CMS-1, D5F149, D5F150, and D5F153 has been assembled. We have recently reported strong linkage disequilibrium with Type I SMA for two of these STRs, indicating that the gene is located in close proximity to or within our cosmid clone array.

Base Sequence↗
PubMed2002

Spinal muscular atrophy in black South Africans: concordance with the universal SMN1 genotype.

Only one study has reported on the genetic basis of spinal muscular atrophy (SMA) in South African subjects. This was conducted in the Johannesburg region and has suggested that black South Africans only (indigenous Africans) differ from the norm. We have explored this further by DNA studies in 30 unrelated and racially diverse patients who reside in the Western Cape, and who were assessed as SMA subjects according to the internationally accepted inclusion criteria for SMA. These subjects were seen at the neurology clinic at Red Cross Children's Hospital in Cape Town during the period 1980-2001. Four had the type 1 form of SMA, 16 had type 2 and 10 had type 3. 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. This study shows that all patients from the Western Cape, which included 12 black South Africans, are no different genetically or phenotypically from the internationally recognized form of typical SMA.

Black People↗
PubMed2006

[The expression of SMN2 gene mRNA in neuron-like cells derived from patients with spinal muscular atrophy].

OBJECTIVE: To detect the difference of SMN2 mRNA expression between the neuron-like cells (NLCs) derived from patients with spinal muscular atrophy (SMA). METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to diagnose the patients with SMA and the controls. Mesenchymal stem cells (MSCs) were induced into neuron-like cells which become the models of neurons. The transcripts of SMN2 were testified with RT-PCR combined with sequencing. RESULTS: Two bands (266 bp and 212 bp) were found in the gel picture of RT-PCR and the band of 266 bp was the full length transcript (fl-SMN mRNA). The band of 212 bp was testified by sequencing to be deletion of the exon 7, which was the production of alternative splicing (skipping exon 7, SMNDelta7 mRNA). The expression of fl-SMN mRNA accounted for 23.2% of the total SMN mRNA in the SMA patients, being much lower than the rate in the controls (82.0%). In contrast, 76.8% of SMN gene transcripts was SMNDelta7 mRNA in the SMA patients, being much higher than the rate of 18% in the controls. CONCLUSIONS: Alternative splicing exists in SMN2 gene transcription, that is, exon 7 is skipped during the processing of SMN2 mRNA in the NLCs of SMA patients, which is one of the reasons of the full-length SMN protein lacking.

Adolescent↗
PubMed1999

Gemin3: A novel DEAD box protein that interacts with SMN, the spinal muscular atrophy gene product, and is a component of gems.

The survival of motor neurons (SMN) gene is the disease gene of spinal muscular atrophy (SMA), a common motor neuron degenerative disease. The SMN protein is part of a complex containing several proteins, of which one, SIP1 (SMN interacting protein 1), has been characterized so far. The SMN complex is found in both the cytoplasm and in the nucleus, where it is concentrated in bodies called gems. In the cytoplasm, SMN and SIP1 interact with the Sm core proteins of spliceosomal small nuclear ribonucleoproteins (snRNPs), and they play a critical role in snRNP assembly. In the nucleus, SMN is required for pre-mRNA splicing, likely by serving in the regeneration of snRNPs. Here, we report the identification of another component of the SMN complex, a novel DEAD box putative RNA helicase, named Gemin3. Gemin3 interacts directly with SMN, as well as with SmB, SmD2, and SmD3. Immunolocalization studies using mAbs to Gemin3 show that it colocalizes with SMN in gems. Gemin3 binds SMN via its unique COOH-terminal domain, and SMN mutations found in some SMA patients strongly reduce this interaction. The presence of a DEAD box motif in Gemin3 suggests that it may provide the catalytic activity that plays a critical role in the function of the SMN complex on RNPs.

Amino Acid Motifs↗
PubMed2003

Allele-specific amplification of exon 7 in the survival motor neuron (SMN) genes for molecular diagnosis of spinal muscular atrophy.

There are two highly homologous survival motor neuron (SMN) genes in humans but molecular defects in the SMN1 gene cause spinal muscular atrophy (SMA). More than 90% of SMA patients are shown to have a homozygous deletion of exon 7 in the SMN1 gene. Therefore, a simple test for exon 7 deletion would be very useful in the molecular diagnosis of SMA. However, limited methods are available, and most of these methods utilize expensive instruments and consumables. Here, we describe a simple allele-specific PCR test, which can be performed using standard equipment in DNA laboratories. The principle of the test is based on a single nucleotide difference (C versus T) between the exon 7 of SMN1 and SMN2 genes. Using allele-specific primers, two PCR amplifications are performed for each sample to amplify a 404-bp diagnostic fragment, and consequent electrophoresis of PCR products on agarose gel provides definitive information concerning the exon 7 deletion To rule out false negatives, a 500-bp fragment from the N-acetyltransferase gene was coamplified as an internal control in each test. We have, so far, analyzed 41 SMA samples with our method, and tested the validity of results using an independent restriction fragment length polymorphism (RFLP) method. Genotyping results obtained by both methods were in complete agreement for all of the samples analyzed. Our method can also be used to detect heterozygous deletion of exon 7 in SMN genes, if the relative intensities of the diagnostic and internal control bands are determined.

Alleles↗