Alternative titles; symbols
SNOMEDCT: 111502003; ORPHA: 272, 588, 899; DO: 0050559;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q31.2 | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 | 253800 | Autosomal recessive | 3 | FKTN | 607440 |
A number sign (#) is used with this entry because this form of congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A4; MDDGA4), previously designated Fukuyama congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), or muscle-eye-brain disease (MEB), is caused by homozygous or compound heterozygous mutation in the gene encoding fukutin (FKTN; 607440) on chromosome 9q31.
Mutation in the FKTN gene can also cause a less severe congenital muscular dystrophy-dystroglycanopathy without impaired intellectual development (type B4; MDDGB4; 613152) and a limb-girdle muscular dystrophy-dystroglycanopathy (type C4; MDDGC4; 611588).
MDDGA4 is a severe autosomal recessive muscular dystrophy-dystroglycanopathy with characteristic brain and eye malformations, seizures, and mental retardation. Cardiac involvement in FCMD/MEB occurs in the second decade of life in those who survive. FKTN-related Walker-Warburg syndrome is a more severe manifestation of the disorder, with death usually in the first year of life. These entities are part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007; Muntoni and Voit, 2004; Muntoni et al., 2008).
For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).
This disorder has been described as FCMD/muscle-eye-brain disease (MEB) and the more severe Walker-Warburg syndrome; these designations have been retained here when used in the literature.
Fukuyama Congenital Muscular Dystrophy/FKTN-Related Muscle-Eye-Brain Disease
Fukuyama et al. (1960) described a novel form of congenital muscular dystrophy. Parental consanguinity was present in 6 families; in 2 sibships, multiple cases were observed. Fukuyama et al. (1981) stated that more than 200 cases had been recognized clinically in Japan. Patients manifest generalized muscle weakness and hypotonia from early infancy and most are unable to walk without support. All are mentally retarded and some have seizures, abnormal electroencephalograms, and abnormal CT scans. The brain malformations in FCMD include cerebral and cerebellar micropolygyria, fibroglial proliferation of the leptomeninges, hydrocephalus, focal interhemispheric fusion, and hypoplasia of the corticospinal tracts.
Histologic changes in skeletal muscle were similar to those of Duchenne muscular dystrophy (DMD; 310200) (Nonaka et al., 1982). Caucasian patients were studied by Dambska et al. (1982). Miura and Shirasawa (1987) described severe myocardial fibrosis in the autopsy of a 17-year-old Japanese male. Aida et al. (1994) demonstrated cerebellar polymicrogyria and the presence of cerebellar cysts related to the polymicrogyria in 23 of 25 patients with congenital muscular dystrophy. These 2 changes on MRI are distinctive enough to suggest the radiologic diagnosis of this disorder.
Yoshioka and Kuroki (1994) performed clinical and genetic studies in 41 families with FCMD in Japan in an attempt to distinguish it from the Walker-Warburg syndrome and muscle-eye-brain disease, both of which, like FCMD, show an association of type II lissencephaly and ocular anomalies. Two or more children were affected in 9 families. Parental consanguinity was documented in 5 of the 32 sporadic cases and in none of the familial cases. In evaluations of 7 sib pairs, a difference between sibs in motor ability was apparent in 4. Mental status also showed wide variation. The EEG findings differed in 2 of 7 sib pairs. The familial FCMD patients showed relatively more severe motor disability than that in the sporadic FCMD patients, whereas the status in regard to mental function and convulsions showed no significant difference in the 2 groups. In 1 family, hydrocephalus was found in only 1 of the sibs; in addition, this patient showed encephalocele and retinal detachment at birth. Yoshioka and Kuroki (1994) emphasized the broad clinical spectrum of FCMD and the phenotypic overlap with mild WWS and MEB disease.
Toda et al. (1995) used polymorphic microsatellites flanking the FCMD locus on 9q31-q33 (see MAPPING) to study a family in which 3 sibs were affected with either FCMD or WWS. One sib was labeled as FCMD because he showed severe hypotonia with dystrophic findings on a muscle biopsy, in addition to pachygyria on computed tomographic scan. At age 3 years, the patient developed retinal detachment in both eyes. The second pregnancy resulted in a male infant with anencephaly who survived for 5 minutes. At birth, the third sib exhibited pachygyria, cephalocele, hydrocephalus, bilateral retinal detachment, elevated serum creatine kinase, and arthrogryposis multiplex congenita, all features consistent with Walker-Warburg syndrome. Haplotype analysis demonstrated identity of each allele in the 2 surviving sibs. The parents were nonconsanguineous, and the disease-related haplotypes were different on the 2 alleles of the patients. Toda et al. (1995) presented this as evidence that the 2 disorders may be allelic.
Godfrey et al. (2007) identified 1 patient with FKTN-related FCMD/MEB among a larger study of 92 probands with muscular dystrophy and evidence of a dystroglycanopathy. Although clinical details were limited, the patient had infantile onset, muscle hypertrophy, increased serum creatine kinase, and low IQ. He only achieved sitting. There were no eye abnormalities, but brain MRI showed cerebellar cysts, white matter abnormalities, and hydrocephalus. As part of the larger study, Godfrey et al. (2007) defined FCMD/MEB as congenital onset of muscular dystrophy with fronto-parietal pachygyria, cerebellar dysplasia, and frequent flattening of the pons and brainstem. Eye abnormalities are often seen, and rare patients may acquire the ability to walk or learn a few words.
Vuillaumier-Barrot et al. (2009) reported 2 Portuguese sisters with mental retardation and muscular dystrophy associated with compound heterozygous mutations in the FKTN gene (A170E, 607440.0016; Y371C, 607440.0017). Both had congenital hip dislocation, congenital hypotonia, and delayed motor development. Muscle weakness was diffuse and progressive with axial and proximal limb predominance and moderate facial involvement; both had significantly increased serum creatine kinase. One sister lost the ability to walk in the first decade of life and developed multiple contractures and severe respiratory insufficiency. She was mentally retarded and had epileptic seizures from age 13 years. The other sister had knee contractures from the first year of life, spinal rigidity, and scoliosis. She developed severe and progressive restrictive respiratory insufficiency and nondilated left ventricular dysfunction in her teens. At age 19 years, she had diffuse amyotrophy, severe multiple joint contractures, and a stiff hyperextended neck. Both were mentally retarded, but 1 had significantly better verbal abilities. Brain MRI showed brainstem atrophy, marked cerebellar vermis hypoplasia and cysts, and cortical brain atrophy. One patient had cerebellar polymicrogyria. Vuillaumier-Barrot et al. (2009) commented that few patients outside of Japan had been reported with this disorder.
Tunc et al. (2009) reported a female infant with FCMD, born of consanguineous Turkish parents, who had severe hypotonia and abnormal limb movements. Just after birth, she showed rhythmic and jerky movements of all 4 limbs, both spontaneously and in response to stimulus, but these were associated with a normal EEG. The findings were consistent with hyperekplexia (see HKPX1, 149400). Brain imaging showed absent corpus callosum, lissencephaly, pachygyria, ventricular dilatation, subcortical white matter abnormalities, and brainstem and cerebellar hypoplasia. She died at day 15.
Xiong et al. (2009) reported a Chinese boy with FCMD. He showed hypotonia from birth, achieved head control at age 2 years, and sat unsupported at age 4 years, but was unable to slide on his buttocks. He developed progressive knee and ankle contractures after age 1 year. He had facial muscle and generalized muscle weakness with severe muscle atrophy, but hypertrophy of the calf muscle. Brain MRI showed patchy periventricular hyperintensities, frontal lobe polymicrogyria, cerebellar cysts, and cerebellar and brainstem hypoplasia. He had an IQ of 52 and spoke only a few words. Muscle biopsy showed prominent dystrophic features and decreased alpha-dystroglycan staining. Genetic analysis identified compound heterozygosity for 2 mutations in the fukutin gene: the common Japanese founder allele (607440.0001) and R47X (607440.0002). Although the boy's parents were born in Henan and Shanxi Provinces and had no known Japanese ancestry, haplotype analysis showed that both mutant alleles were on Japanese-derived haplotypes.
FKTN-Related Walker-Warburg Syndrome
Silan et al. (2003) reported a Turkish patient with a severe congenital muscular dystrophy phenotype most closely resembling Walker-Warburg syndrome. The patient presented at birth with hypotonia, hydrocephalus, respiratory difficulties, ocular abnormalities, and elevated muscle enzymes, and died on the tenth day of life. Postmortem examination revealed severe malformations of the central nervous system, including agyria and cortical disorganization, and congenital muscular dystrophy.
Beltran-Valero de Bernabe et al. (2003) reported a Turkish patient with Walker-Warburg syndrome. Born to second-degree consanguineous parents, the patient had macrocephaly, anterior chamber abnormalities, severe hypotonia, and severe brain malformations, including hydrocephalus, agyria/pachygyria, absent corpus callosum and cerebellar vermis, and white matter hyperlucencies. The patient died at 4.5 months of age.
Godfrey et al. (2007) identified 1 patient with FKTN-related WWS among a larger study of 92 probands with muscular dystrophy and evidence of a dystroglycanopathy. Although clinical details were limited, the patient had neonatal onset, contractures, muscle hypertrophy, and increased serum creatine kinase. Eye abnormalities included retinal detachment and microphthalmia. Brain MRI showed cerebellar hypoplasia, white matter abnormalities, hydrocephalus, and brainstem involvement. As part of the larger study, Godfrey et al. (2007) defined WWS as prenatal onset or onset of birth of absence of motor development and severe structural brain abnormalities, including complete agyria or severe lissencephaly, marked hydrocephalus, severe cerebellar involvement, and complete or partial absence of the corpus callosum. Common eye abnormalities included congenital cataracts, microphthalmia, and buphthalmos. Death usually occurred before 1 year of age. Genetic analysis identified a homozygous truncating mutation in the FKTN gene (R307X; 607440.0018).
Cotarelo et al. (2008) described a Spanish female infant, born of nonconsanguineous parents, who was diagnosed with Walker-Warburg syndrome and died on day 5 of life after suffering respiratory apnea and bradycardia. She had a dysmorphic face with low-set malformed ears, left preauricular tag, thoracic hemivertebrae, and cardiac defects. Brain CT scan showed overriding cranial bones, severe left microphthalmia, monolobar holoprosencephaly, and internal and external hydrocephalus. Cortex and white matter could not be differentiated, and no details could be observed in the posterior fossa. At autopsy, the medial aspect of the brain showed an interhemispheric cyst, incomplete cleavage of the thalamus and corpora quadrigemina, an absent corpus callosum, and rhombencephalic hypoplasia. Punctate hemorrhages were seen in the parenchyma, and ventriculitis was identified. An atrial septal defect (foramen ovale), double subaortic ventricular defect, hypoplastic left ventricle outlet, stenotic pulmonary valve, and infundibular transposition of the great vessels with no innominate vein were also found. The eyes were malformed and exhibited retinal dysplasia.
The involvement of multiple sibs of both sexes and parental consanguinity reported by Fukuyama et al. (1960) supported autosomal recessive inheritance.
Toda et al. (1993) performed genetic linkage analysis with polymorphic microsatellite markers in 21 FCMD families, 13 of which had consanguineous marriages. Significant lod scores were found with 3 loci on 9q31-q33. Multipoint analysis placed the FCMD gene in the interval between D9S58 and D9S59, with a maximum location score of 39.0. Homozygosity mapping supported the assignment. In a nonconsanguineous sibship in which 1 sib was thought to have FCMD and another sib was thought to have WWS, Toda et al. (1995) found linkage to the FCMD locus on chromosome 9q31-q33, suggesting that they may be allelic disorders, or at least caused by the same gene in this family.
Toda et al. (1996) refined the map location of FCMD to a 5-cM region between D9S127 and D9S2111. They reported that there is linkage disequilibrium between FCMD and markers in 9q31. Haplotype analysis using the markers D9S2105, D9S2107, and D9S172 indicated that most FCMD-bearing chromosomes in Japanese pedigrees were derived from a single ancestral founder. On the basis of haplotype analysis, Toda et al. (1996) concluded that the FCMD gene most likely lies on 9q31 within a less than 100-kb region containing the D9S2107 marker. They suggested that the muscle-specific receptor tyrosine kinase gene (MUSK; 601296) reported by Valenzuela et al. (1995) is a candidate FCMD gene since its map location overlaps with that of FCMD. Miyake et al. (1997) described YAC and cosmid contigs encompassing the FCMD candidate region on 9q31.
FCMD is characterized clinically by a peak motor function that, at best, usually allows patients to sit unassisted or slide on the buttocks. However, a small fraction of patients acquire the ability to walk unassisted. Looking for genetic heterogeneity in FCMD, Kondo-Iida et al. (1997) performed linkage analysis in 10 families with ambulant cases using DNA markers flanking the FCMD locus. Linkage and linkage disequilibrium were found, suggesting homogeneity. The authors further conducted haplotype analysis in a family in which 1 sib was ambulant, whereas the other was not. They found that the sibs had the same haplotype at 9 marker loci spanning 23.3 cM surrounding the FCMD locus. On the basis of these results, Kondo-Iida et al. (1997) concluded that, genetically, ambulant cases are part of the FCMD spectrum.
Kobayashi et al. (1998) described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived from a single ancestor. They reported that there is a retrotransposal insertion (607440.0001) of tandemly repeated sequences in the FKTN gene in all FCMD chromosomes carrying the founder haplotype (87%). The authors stated that FCMD is the first human disease known to be caused by an ancient retrotransposal integration. Two independent point mutations (607440.0002 and 607440.0003) in patients with FCMD confirmed that mutation in this gene is responsible for FCMD.
Kondo-Iida et al. (1999) performed a systematic analysis of the FKTN gene in 107 unrelated patients and identified 4 novel nonfounder mutations in 5 of them: 1 missense, 1 nonsense, 1 L1 insertion (607440.0004), and one 1-bp insertion (607440.0005).
Silan et al. (2003) identified a homozygous truncating mutation in the FKTN gene (607440.0006) in a Turkish patient with WWS. The first-cousin parents and an unaffected brother were heterozygous for the mutation. Silan et al. (2003) noted that this was the first reported case of a fukutin mutation found outside the Japanese population and the first reported case of a homozygous nonfounder mutation, which was believed to be embryonic lethal. Although the patient may be considered to have FCMD due to the mutation in the FKTN gene, the authors noted that classification of the disease in this patient could be difficult because the phenotype was slightly different and more closely resembled Walker-Warburg syndrome.
In a Turkish patient with WWS, Beltran-Valero de Bernabe et al. (2003) identified a homozygous nonsense mutation in the FKTN gene (607440.0007). The authors noted that the phenotype in this patient was more consistent with WWS than with FCMD, and established a genotype/phenotype correlation for fukutin mutations that cause complete loss of protein function.
In a Spanish infant with WWS, Cotarelo et al. (2008) identified compound heterozygosity for 2 mutations in the FKTN gene (607440.0012 and 607440.0013). In cell lines from unrelated Ashkenazi Jewish parents and their son, who was diagnosed with WWS, Cotarelo et al. (2008) identified a 1-bp insertion in the FKTN gene (607440.0005) that had previously been identified in compound heterozygosity in patients with FCMD and a less severe form of muscular dystrophy (611588). The son was homozygous for the insertion, and the unaffected parents were heterozygous carriers.
Kondo-Iida et al. (1999) noted that the frequency of severe phenotypes, including Walker-Warburg syndrome-like manifestations such as hydrocephalus and microphthalmia, was significantly higher among probands who were compound heterozygotes carrying a point mutation on one allele and a founder mutation on the other, than among probands who were homozygous for the 3-kb retrotransposon (607440.0001). Remarkably, they detected no FCMD patients with nonfounder (point) mutations on both alleles of the gene, suggesting that such cases might be embryonic lethal. This could explain why few FCMD cases are reported in non-Japanese populations. Their results provided strong evidence that loss of function of fukutin is the major cause of FCMD, and appeared to shed some light on the mechanism responsible for the broad clinical spectrum seen in this disorder.
To establish a genotype-phenotype correlation, Saito et al. (2000) performed haplotype analysis using microsatellite markers closest to the FKTN gene in 56 Japanese FCMD families, including 35 families whose children were diagnosed as having FCMD with the typical phenotype, 12 families with a mild phenotype, and 9 families with a severe phenotype. Of the 12 probands with the mild phenotype, 8 could walk and the other 4 could stand with support; 10 cases were homozygous for the ancestral founder haplotype, whereas the other 2 were heterozygous for the haplotype. Of the 9 severely affected patients who had never acquired head control or the ability to sit without support, 3 had progressive hydrocephalus, 2 required a shunt operation, and 7 had ophthalmologic abnormalities. Haplotype analysis showed that 8 of the 9 cases of the severe phenotype were heterozygous for the ancestral founder haplotype, and the other 1 homozygous for the haplotype.
Saito et al. (2000) confirmed that at least 1 chromosome in each of the 56 FCMD patients had the ancestral founder haplotype. The rate of heterozygosity for this haplotype was significantly higher in severe cases than in typical or mild cases (P less than 0.005). Severe FCMD patients appeared to be compound heterozygotes for the founder mutation and another mutation.
Kobayashi et al. (1998) reported that the retroposon sequence insertion (607440.0001) was found in 125 (87%) of 144 FCMD chromosomes, whereas it was found in only 1 of 176 chromosomes in unrelated normal individuals; the frequency of 1 in 88 individuals corresponded well to that of FCMD carriers in the Japanese population.
Watanabe et al. (2005) developed a rapid PCR-based diagnostic method for detecting the FCMD retroposon insertion mutation using 3 primers simultaneously. Fifteen founder chromosomes were detected among 2,814 Japanese individuals. Heterozygous carriers were identified in various regions throughout Japan, with a carrier frequency of approximately 1 in 188. The insertion mutation was found in 1 in 935 Korean individuals but not among 203 Mongolians and 766 mainland Chinese, suggesting that FCMD carriers are rare outside Japan.
Takada et al. (1984) rejected the suggestion that the myopathy is secondary to the CNS changes for several reasons, including the finding that the morphologic changes are dystrophic in nature. They postulated a pleiotropic gene accounting for the lesions in both skeletal muscles and the nervous system. As reviewed by Beggs et al. (1992), a few patients with the clinical diagnosis of FCMD have been shown to have abnormalities of dystrophin (300377) on skeletal muscle biopsy. Epidemiologic data suggested that only 1 in about 3,500 males with autosomal recessive FCMD should have abnormal dystrophin; however, abnormal dystrophin was observed in 3 of 23 FCMD males. As an explanation, Beggs et al. (1992) suggested that dystrophin and the FCMD gene product interact and that the early onset and greater severity of the phenotype in these patients, relative to Duchenne muscular dystrophy, was due to their being heterozygous for the FCMD mutation in addition to being hemizygous for DMD. This combined genotype was predicted to occur in 1 in about 175,000 Japanese males. The model might explain some of the clinical and pathologic variability seen in FCMD and could have potential implications for understanding the inheritance of other autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products. The sex ratio in such instances might display a deviation from 1:1.
Kobayashi et al. (1998) could not demonstrate fukutin in skeletal muscle using polyclonal and monoclonal antibodies. In transfected COS-7 cells, they found evidence of colocalization with a Golgi marker and a granular cytoplasmic distribution, suggesting that fukutin passes through the Golgi before being packaged into secretory vesicles. The signal was not seen at the plasma membrane, however, where most proteins responsible for muscular dystrophies are located. Kobayashi et al. (1998) suggested that fukutin may be located in the extracellular matrix, where it interacts with and reinforces a large complex encompassing the outside and inside of muscle membranes; alternatively, as a secreted protein, fukutin may cause muscular dystrophy by an unknown mechanism. A major manifestation of FCMD is micropolygyria (type II lissencephaly), in which neuronal lamination of normal 6-layered cortex is lacking because of a defect in the migration of neurons. Other genes implicated in cortical dysgenesis disorders that appear to function in the migration and assembly of neurons during cortical histogenesis include DCX (300121), LIS1 (601545), and RELN (600514).
Matsumura et al. (1993) reported that dystrophin-associated proteins such as alpha-dystroglycan (DAG1; 128239) have abnormally low expression in FCMD. DAG1 is a cell surface protein that plays an important role in the assembly of the extracellular matrix in muscle, brain, and peripheral nerves by linking the basal lamina to cytoskeletal proteins. Using PCR, immunohistochemistry, and immunoblotting to analyze samples from patients with FCMD, Hayashi et al. (2001) confirmed a deficiency of fukutin and found marked deficiency of highly glycosylated DAG1 in skeletal and cardiac muscle and reduced amounts of DAG1 in brain tissue. Beta-dystroglycan was normal in all tissues examined. These findings supported the suggestion that fukutin deficiency affects the modification of glycosylation of DAG1, which then cannot localize or function properly and may be degraded or eluted from the extracellular surface membrane of the muscle fiber. Hayashi et al. (2001) concluded that this disruption underlies the developmental, structural, and functional damage to muscles in patients with FCMD. Michele et al. (2002) demonstrated in both MEB disease and FCMD patients that alpha-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in the diseases directly abolishes binding activity of dystroglycan for the ligands laminin (see 156225), neurexin (see 600565), and agrin (103320).
Taniguchi et al. (2006) performed histologic examination and cDNA microarray analysis of skeletal muscle biopsy specimens from 4 patients with FCMD and 1 with MDC1A (607855) at various ages during childhood. Histologic examination showed dystrophic features, fiber size variation, prominent interstitial tissue, and adipose tissue proliferation. Inflammation, necrosis, and regeneration of muscle fibers were less apparent, especially compared to biopsies from patients with DMD. FCMD and MDC1A samples showed increased expression of extracellular matrix genes, such as COL3A1 (120180), THBS4 (600715), and OSF2 (POSTN; 608777), whereas there was downregulation of genes encoding mature muscle components, including MYH7 (160760), TCAP (604488), DES (125660), and MYH1 (160730). Upregulation of gene expression occurred predominantly in muscle fibers and only slightly in fibroblasts. In contrast, a previous microarray analysis of DMD muscle (Noguchi et al., 2003) reported upregulation of genes encoding muscle components, reflecting enhanced active muscle fiber regeneration following degeneration in DMD. Taniguchi et al. (2006) suggested that the primary pathologic feature of FCMD and MDC1A is interstitial fibrosis without muscle degeneration and regeneration, which distinguishes these disorders from DMD.
By gene expression profiling of skeletal muscle from patients with FCMD, Taniguchi et al. (2006) found a pattern suggesting maturational arrest of muscle fibers, with a decrease in developmentally regulated genes, such as the mature myosin heavy chain components MYH1 (160730), MYH2 (160740), and MYH7, and myogenic factors MRF4 (159991) and MYOD1 (159970), as well as upregulated MYOG (159980). RT-PCR analysis showed upregulation of the fetal cholinergic receptor isoform CHRNG (100730). Histologic studies showed an increase in type 2C muscle fibers, which are mainly seen in fetal muscle or regenerating fibers. The results indicated an unbalanced differentiation process. Histologic and electron microscopic analysis of FCMD samples showed aberrant neuromuscular junctions (NMJs), with fewer synaptic folds and secondary clefts than normal, also consistent with maturational arrest. These NMJs also showed functional impairment. Importantly, these changes were also different from that observed in DMD. Overall, the findings suggested that FCMD is not a classic muscular dystrophy, but rather is also characterized by an arrest of development and differentiation of both muscle fibers and the NMJ. Taniguchi et al. (2006) hypothesized that hypoglycosylated DAG1 interferes with proper DAG1 aggregation in critical regions during muscle development.
Taniguchi-Ikeda et al. (2011) demonstrated that aberrant mRNA splicing, induced by SINE-VNTR-Alu (SVA) exon trapping, underlies the molecular pathogenesis of FCMD. Quantitative mRNA analysis pinpointed a region that was missing from transcripts in patients with FCMD. This region spans part of the 3-prime end of the fukutin coding region, a proximal part of the 3-prime UTR, and the SVA insertion. Correspondingly, fukutin mRNA transcripts in patients with FCMD and SVA knockin model mice were shorter than the expected length. Sequence analysis revealed an abnormal splicing event, provoked by a strong acceptor site in SVA and a rare alternative donor site in fukutin exon 10. The resulting product truncates the fukutin carboxy terminus and adds 129 amino acids encoded by the SVA. Introduction of antisense oligonucleotides targeting the splice acceptor, the predicted exonic splicing enhancer, and the intronic splicing enhancer prevented pathogenic exon trapping by SVA in cells of patients with FCMD and in model mice, rescuing normal fukutin mRNA expression and protein production. Antisense oligonucleotide treatment also restored fukutin functions, including O-glycosylation of alpha-dystroglycan and laminin binding by alpha-dystroglycan. Moreover, Taniguchi-Ikeda et al. (2011) observed exon trapping in other SVA insertions associated with disease (hypercholesterolemia, neutral lipid storage disease) and human-specific SVA insertion in a novel gene. Thus, Taniguchi-Ikeda et al. (2011) concluded that, although splicing into SVA is known, they discovered in human disease a role for SVA-mediated exon trapping and demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD and other SVA-mediated diseases.
Michele et al. (2002) showed that the posttranslational biochemical and functional disruption of alpha-dystroglycan in humans is recapitulated in the muscle and central nervous system of mutant myodystrophy (myd) mice, which have a mutation in the Large gene (603590). They demonstrated that myd mice have abnormal neuronal migration in the cerebral cortex, cerebellum, and hippocampus, and show disruption of the basal lamina. In addition, dystroglycan in myd mice targets proteins to functional sites in brain through its interactions with extracellular matrix proteins. Michele et al. (2002) suggested that at least 3 mammalian genes function within a convergent posttranslational processing pathway during the biosynthesis of dystroglycan and that abnormal dystroglycan-ligand interactions underlie the pathogenic mechanism of muscular dystrophy with brain abnormalities.
Kanagawa et al. (2009) generated a mouse model of FCMD by introducing the disease-causing retrotransposon into the mouse Fktn gene. Knockin mice exhibited hypoglycosylated alpha-dystroglycan; however, no signs of muscular dystrophy were observed. More sensitive methods detected minor levels of intact alpha-dystroglycan, and solid-phase assays determined laminin (see 156225)-binding levels to be 50% of normal. In contrast, intact alpha-dystroglycan was undetectable in the dystrophic Large(myd) mouse, and laminin-binding activity was markedly reduced. This suggested that a small amount of intact alpha-dystroglycan may be sufficient to maintain muscle cell integrity in knockin mice. Transfer of fukutin into knockin mice restored glycosylation of alpha-dystroglycan. Transfer of Large produced laminin-binding forms of alpha-dystroglycan in both knockin mice and the Pomgnt1 (606822)-mutant mouse, which is another model of dystroglycanopathy. Kanagawa et al. (2009) suggested that even partial restoration of alpha-dystroglycan glycosylation and laminin-binding activity by replacing or augmenting glycosylation-related genes may effectively deter dystroglycanopathy progression and thus provide therapeutic benefits.
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