Alternative titles; symbols
HGNC Approved Gene Symbol: FKTN
SNOMEDCT: 111502003, 726618007;
Cytogenetic location: 9q31.2 Genomic coordinates (GRCh38) : 9:105,558,130-105,641,118 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q31.2 | Cardiomyopathy, dilated, 1X | 611615 | Autosomal recessive | 3 |
| Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 | 253800 | Autosomal recessive | 3 | |
| Muscular dystrophy-dystroglycanopathy (congenital without impaired intellectual development), type B, 4 | 613152 | Autosomal recessive | 3 | |
| Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 | 611588 | Autosomal recessive | 3 |
The FKTN gene encodes a type II transmembrane protein that is targeted to the Golgi apparatus through an N-terminal signal anchor (Esapa et al., 2002).
On the basis of haplotype analysis, Toda et al. (1996) concluded that the locus for Fukuyama congenital muscular dystrophy (FCMD; 253800) lies within a 100-kb region on chromosome 9q13. By positional cloning, Kobayashi et al. (1998) identified the FKTN gene. The deduced 461-amino acid protein, which they termed fukutin, was expressed in various tissues in normal individuals. The predicted protein contains an N-terminal signal sequence which, together with results from transfection experiments, suggested that fukutin is a secreted protein.
By positional cloning, Kobayashi et al. (1998) identified the FKTN gene on chromosome 9q31.
In transfected COS-7 cells, Kobayashi et al. (1998) found evidence of colocalization of fukutin 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.
Using Northern blot and RT-PCR analysis, Sasaki et al. (2000) determined that the fukutin gene is expressed at similar levels in control fetal and adult brain, but is much reduced in FCMD brains. Tissue in situ hybridization analysis revealed fukutin mRNA expression in migrating neurons, including Cajar-Retzius cells and adult cortical neurons, as well as hippocampal pyramidal cells and cerebellar Purkinje cells. However, no expression was observed in the glia limitans, the subpial astrocytes (which contribute to basement membrane formation), or other glial cells. In the FCMD brain, neurons in regions with no dysplasia showed fair expression, whereas transcripts were nearly undetectable in the overmigrated dysplastic region. The authors hypothesized that fukutin may influence neuronal migration itself rather than formation of the basement membrane.
Alpha-dystroglycan (DAG1; 128239) 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 (see 128239) 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.
Using transfection experiments, Esapa et al. (2002) determined that fukutin and fukutin-related protein (FKRP; 606596) are Golgi-resident proteins and that they are targeted to the medial Golgi apparatus through their N termini and transmembrane domains.
Muscular Dystrophy-Dystroglycanopathy, Types A4, B4, and C4
Mutation in the FKTN gene can cause 3 different forms of muscular dystrophy-dystroglycanopathy (MDDG): a severe congenital form with brain and eye anomalies (type A4; MDDGA4, 253800), formerly designated Fukuyama congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), or muscle-eye-brain disease (MEB); a less severe congenital form without impaired intellectual development (type B4; MDDGB4; 613152); and a milder limb-girdle form (type C4; MDDGC4; 611588), also designated LGMDR13 and LGMD2M.
In Japan, Toda et al. (1996) and Kobayashi et al. (1998) described a haplotype that is shared by more than 80% of chromosomes of patients with Fukuyama congenital muscular dystrophy (FCMD; MDDGA4), indicating that most chromosomes bearing the mutation could be derived from a single ancestor. Kobayashi et al. (1998) reported that there is a retrotransposal insertion (607440.0001) of tandemly repeated sequences within the candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%). The inserted sequence was about 3 kb long and was located in the 3-prime untranslated region (UTR) of the gene. One component of the 3,062-bp insert was a SINE (short interspersed sequence)-type retroposon sequence. Kobayashi et al. (1998) stated that FCMD is the first human disease known to be caused by an ancient retrotransposal integration. In patients with FCMD, Kobayashi et al. (1998) identified 2 independent mutations (607440.0002 and 607440.0003) in the FKTN gene. Watanabe et al. (2005) noted that the insertion was of a class of retroposon referred to as SINE-VNTR-Alu (SVA).
Kondo-Iida et al. (1999) extended the known mutation repertoire of the FKTN gene. In a systematic analysis of the FKTN gene in 107 unrelated patients with FCMD, they found 4 novel nonfounder mutations in 5 patients: 1 missense, 1 nonsense, 1 L1 insertion (607440.0004), and one 1-bp insertion (607440.0005).
In patients with a clinical diagnosis of Walker-Warburg syndrome (MDDGA4), Beltran-Valero de Bernabe et al. (2003) and Silan et al. (2003) independently identified mutations in the FKTN gene (607440.0006 and 607440.0007, respectively).
In cell lines from unrelated Ashkenazi Jewish parents and their son, who was diagnosed with WWS, Cotarelo et al. (2008) identified the 1-bp insertion in the FKTN gene (607440.0005) that had previously been identified in compound heterozygosity in patients with FCMD and FKTN-related muscular dystrophy. The son was homozygous for the insertion, and the unaffected parents were heterozygous carriers. In a Spanish female infant diagnosed with WWS who died at day 5 of life, Cotarelo et al. (2008) identified compound heterozygosity for a missense mutation (G125S; 607440.0012) and a 473-bp deletion (607440.0013) in the FKTN gene.
In 3 patients with limb-girdle muscular dystrophy due to defective glycosylation of dystroglycan (MDDGC4; 611588), Godfrey et al. (2006) identified compound heterozygosity for mutations in the FKTN gene (607440.0005; 607440.0008; 607440.0009). The authors noted that the phenotype was much less severe than that observed in the allelic disorder Fukuyama congenital muscular dystrophy. The patients showed early-onset proximal muscular dystrophy, normal intelligence and brain structure, and favorable response to steroid treatment.
Puckett et al. (2009) identified compound heterozygous mutations in the FKTN gene (A114T, 607440.0014 and F176S, 607440.0015) in 2 brothers of Japanese and Caucasian ancestry with FKTN-related limb-girdle muscular dystrophy (MDDGC4). The phenotype was relatively mild, and there was no cardiac or cognitive involvement. Skeletal muscle biopsy showed defective glycosylation of alpha-dystroglycan.
Godfrey et al. (2007) identified FKTN mutations in 6 of 92 patients with evidence of a muscular dystrophy due to defective glycosylation of alpha-dystroglycan. Only 2 had structural brain anomalies: 1 with WWS and 1 with MEB.
Mercuri et al. (2009) identified compound heterozygosity for 2 mutations in the FKTN gene (R307Q; 607440.0009 and 42delG; 607440.0019) in 1 of 81 Italian patients with congenital muscular dystrophy associated with defective glycosylation of alpha-dystroglycan (MDDGB4; 613152). The patient did not have mental retardation and had no structural brain abnormalities.
Taniguchi-Ikeda et al. (2011) demonstrated that aberrant mRNA splicing, induced by SINE-VNTR-Alu (SVA) exon trapping, underlies the molecular pathogenesis of FCMD (MDDGA4). 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 model mice, rescuing normal fukutin mRNA expression and protein production. Antisense oligonucleotide treatment also restored fukutin functions, including O-glycosylation of alpha-dystroglycan (DAG1; 128239) and laminin (see 156225) 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 had 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.
Using human mutant FKTN constructs with expression in mouse myoblasts, Tachikawa et al. (2012) found that 4 pathogenic missense mutations (A170E, 607440.0016; H172R; H186R; and Y371C, 607440.0017) showed aberrant accumulation in the endoplasmic reticulum (ER) due to protein misfolding and failure of the anterograde pathway, in contrast to wildtype FKTN, which localized to the Golgi apparatus. The POMGNT1 (606822) protein also mislocalized to the ER when coexpressed with mutant FKTN. Low-temperature culture or treatment with curcumin variably corrected the subcellular localization of the missense mutant proteins. Expression studies in Fktn-null mouse embryonic cells showed that the mutant proteins retained normal glycosylation activity, indicating that some disease-causing mutations are pathogenic due to abnormal folding and localization. The findings suggested a therapeutic strategy for certain FKTN mutations.
Dilated Cardiomyopathy 1X
Murakami et al. (2006) analyzed the FKTN gene in 6 Japanese patients with CMD and mild or no limb-girdle muscle involvement (CMD1X; 611615) and identified compound heterozygosity in all for a 3-kb retrotransposal insertion (607440.0001) and another missense mutation (607440.0010 or 607440.0011, respectively).
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.
In a Turkish patient with a severe phenotype that resembled Walker-Warburg syndrome, Silan et al. (2003) identified a homozygous nonfounder mutation in the FKTN gene (607440.0006). The patient died at 10 days of age. The authors noted that this was the first non-Japanese patient to be reported with a fukutin mutation, and that the mutation was the first reported nonfounder homozygous mutation. Beltran-Valero de Bernabe et al. (2003) reported a similar case (see 607440.0007).
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 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 severe cases, 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.
Takeda et al. (2003) reported that chimeric mice generated using embryonic stem cells targeted for both fukutin alleles developed severe muscular dystrophy, with the selective deficiency of alpha-dystroglycan (DAG1; 128239) and its laminin (see 156225)-binding activity. In addition, these mice showed laminar disorganization of the cortical structures in the brain with impaired laminin assembly, focal interhemispheric fusion, and hippocampal and cerebellar dysgenesis. Further, chimeric mice showed anomaly of the lens, loss of laminar structure in the retina, and retinal detachment. The authors concluded that fukutin is necessary for the maintenance of muscle integrity, cortical histiogenesis, and normal ocular development, and suggested a functional linkage between fukutin and alpha-dystroglycan.
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-binding levels to be 50% of normal. In contrast, intact alpha-dystroglycan was undetectable in the dystrophic Large(myd) mouse (see 603590), 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.
Muscular Dystrophy-Dystroglycanopathy (Congenital with Brain and Eye Anomalies), Type A, 4
Kobayashi et al. (1998) found that 87% of mutant alleles causing the autosomal recessive disorder Fukuyama congenital muscular dystrophy (MDDGA4; 253800) carried an insertion of a 3,062-bp transposon, situated in the 3-prime UTR of the FKTN gene.
Most Japanese patients with the retrotransposal insertion in the FKTN gene share a common founder haplotype. By applying 2 methods for the study of linkage disequilibrium between flanking polymorphic markers and the disease locus, and of its decay over time, Colombo et al. (2000) calculated the age of the insertion mutation to be approximately 102 generations (95% CI: 86-117 g), or slightly less. The estimated age dates the most recent common ancestor of the mutation-bearing chromosomes back to the time (or a few centuries before) the Yayoi people began migrating to Japan from the Korean peninsula. FCMD was the first human disease known to be caused primarily by an ancient retrotransposal integration.
Kato et al. (2004) stated that 9 nonfounder mutations had been identified in Japanese FCMD patients. Severe phenotype was significantly more frequent in patients who were compound heterozygotes for a point mutation and the 3-kb founder insertion in the FKTN gene than in homozygotes for the founder mutation. The authors described a PCR-based diagnostic method for rapid detection of the insertion mutation. Using this method, they screened 18 FCMD patients and found 16 homozygotes and 2 heterozygotes for the insertion. In the general Japanese population, they found that 6 of 676 persons were heterozygous carriers. Furthermore, they found 3 homozygotes for the FCMD founder mutation among 97 patients who had been said to have probable Duchenne muscular dystrophy (310200) or Becker muscular dystrophy (300376) (DMD/BMD) without any mutation in the DMD gene (300377). On the other hand, there were no FCMD homozygotes but 4 heterozygous carriers among 335 patients with DMD mutations.
By sequence analysis, Watanabe et al. (2005) characterized the insertion mutation and found that it was enclosed by target-site duplications at both ends. They noted that the sequence motif was characteristic of a class of retroposon referred to as SINE-VNTR-Alu (SVA).
Watanabe et al. (2005) established a rapid PCR-based diagnostic method using 3 primers simultaneously in order to detect the 3,062-bp retrotransposal insertion. 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 of Japan.
Xiong et al. (2009) reported a Chinese boy with FCMD who was compound heterozygous for 2 mutations in the fukutin gene: the common 3-kb retroposon insertion 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.
Cardiomyopathy, Dilated, 1X
In 6 Japanese patients from 4 families with dilated cardiomyopathy and mild or no limb-girdle involvement (CMD1X; 611615), Murakami et al. (2006) identified compound heterozygosity in all for the 3-kb retroposon insertion and another missense mutation: Q358P (607440.0010) or R179T (607440.0011), respectively.
Kobayashi et al. (1998) searched for inactivating mutations in the FKTN gene in patients with Fukuyama congenital muscular dystrophy (MDDGA4; 253800) lacking the haplotype indicative of the 3-kb insertion (607440.0001) on 1 chromosome. In a total of 6 families, the noninsertion-bearing chromosome showed a nonsense mutation in the FKTN gene: a C-to-T transition at base 250, resulting in premature termination (CGA to TGA; arg47 to ter).
Kobayashi et al. (1998) found that a girl with Fukuyama congenital muscular dystrophy (MDDGA4; 253800) had inherited the common retrotransposal insertion mutation (607440.0001) from her Japanese mother and a 2-bp deletion at bases 298-299 (codon 63), causing a frameshift and a premature stop at codon 75, from her American father (of English and German extraction).
In 2 unrelated patients with unusually severe FCMD (MDDGA4; 253800), Kondo-Iida et al. (1999) detected a 1.2-kb L1 insertion in the FKTN gene. Each patient carried the founder 3-kb retrotransposal insertion (607440.0001) on one allele and a distinctive haplotype on the other. Sequence analysis revealed that the 3-prime region of an L1 repetitive element had been inserted 24 basepairs before the intron 7-exon 8 boundary. The patients' RNA was tested for the effects of the insertion by means of reverse transcriptase-PCR analysis, using primers that amplified exons 5-10. Products of various sizes were obtained, suggesting exon skipping.
In a girl with severe FCMD (MDDGA4; 253800) including microphthalmia, Kondo-Iida et al. (1999) identified a 1-bp insertion (1279insA) in exon 9 of the FKTN gene, causing a frameshift and a premature stop at codon 403. The patient carried the founder insertion (607440.0001) from her mother; however, the 1-bp insertion could not be detected in the father by either SSCP or by direct sequencing, leading Kondo-Iida et al. (1999) to conclude that this was the first example of a de novo mutation.
In a cell line from an Ashkenazi Jewish male diagnosed with Walker-Warburg syndrome (MDDGA4), Cotarelo et al. (2008) identified homozygosity for a 1-bp insertion within a stretch of 6 adenine residues in exon 9 (1160_1168insA). Cell lines from the unrelated, unaffected parents revealed that they were heterozygous carriers of the insertion.
In 2 sibs and an unrelated child with FKTN-related limb-girdle muscular dystrophy (MDDGC4; 611588), Godfrey et al. (2006) identified compound heterozygosity for mutations in the FKTN gene. All 3 children had a 1-bp insertion in exon 9 (1167insA), which the authors stated was the same mutation as that identified by Kondo-Iida et al. (1999). The insertion was predicted to result in a frameshift at phe390 and premature termination, followed by nonsense-mediated decay of the mRNA transcript. The second mutant allele identified was a 1-bp deletion (607440.0008) in 1 child and a missense mutation (R307Q; 607440.0009) in 2 sibs. The patients showed early-onset proximal muscular dystrophy, normal intelligence and brain structure, and favorable response to steroid treatment.
In a Turkish patient with a severe congenital muscular dystrophy phenotype most closely resembling Walker-Warburg syndrome (MDDGA4; 253800), Silan et al. (2003) identified a homozygous 1-bp insertion (504insT) in exon 5 of the FKTN gene. The first-cousin parents and an unaffected brother were heterozygous for the mutation. 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. 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 Fukuyama congenital muscular dystrophy because of the mutation in the FKTN gene, the authors noted that classification of the disease in this patient may be difficult because the phenotype is slightly different and resembles Walker-Warburg syndrome.
In a Turkish patient diagnosed with Walker-Warburg syndrome (MDDGA4; 253800), Beltran-Valero de Bernabe et al. (2003) identified a homozygous gln116-to-ter (Q116X) mutation in the FKTN gene. Born to second-degree consanguineous parents, the patient had macrocephaly, abnormal eyes, severe hypotonia, and severe brain malformations, including hydrocephalus, agyria/pachygyria, absent corpus callosum and cerebellar vermis, and white matter hyperlucencies. The authors noted that the phenotype in this patient was more consistent with Walker-Warburg syndrome than with Fukuyama congenital muscular dystrophy, and established a genotype/phenotype correlation for fukutin mutations that cause complete loss of protein function.
In a patient with FKTN-related limb-girdle muscular dystrophy and normal intelligence (MDDGC4; 611588), Godfrey et al. (2006) identified compound heterozygosity a 1-bp deletion (1363delG) in exon 10 of the FKTN gene, resulting in a frameshift at asp455 and premature termination, and a 1-bp insertion (607440.0005). Functional expression studies showed that the 1363delG mutant protein was expressed and localized correctly within the cell.
In 2 sibs with FKTN-related limb-girdle muscular dystrophy (MDDGC4; 611588) without mental retardation, Godfrey et al. (2006) identified compound heterozygosity for a 920G-A transition in exon 8 of the FKTN gene, resulting in an arg307-to-gln (R307Q) substitution, and a 1-bp insertion (607440.0005). Functional expression studies showed that the R307Q mutant protein was expressed and localized correctly within the cell.
Mercuri et al. (2009) identified compound heterozygosity for 2 mutations in the FKTN gene (R307Q and 42delG; 607440.0019) in 1 of 81 Italian patients with congenital muscular dystrophy (MDDGB4; 613152) associated with defective glycosylation of alpha-dystroglycan. The patient did not have mental retardation and had no structural brain abnormalities.
Vuillaumier-Barrot et al. (2009) identified a homozygous R307Q mutation in a Turkish girl with a moderately severe form of muscular dystrophy. She had delayed motor development, pes equinovarus, increased serum creatine kinase, generalized proximal muscle weakness, and diffuse muscle wasting of the calves. The disorder was progressive, and she lost ambulation at 11 years and developed contractures. Intelligence and brain MRI were normal.
In a 30-year-old Japanese man and his 33-year-old sister with dilated cardiomyopathy (CMD1X; 611615), Murakami et al. (2006) identified compound heterozygosity for 2 mutations in the FKTN gene: the 3-kb retroposon insertion (607440.0001) and a 1073A-C transversion, resulting in a gln358-to-pro (Q358P) substitution at a highly conserved residue. The brother was diagnosed with idiopathic dilated cardiomyopathy and congestive heart failure at 17 years of age and underwent cardiac transplantation at age 18; he began having slowly progressive proximal muscle weakness of the lower extremities at 24 years of age, and by age 30, he had calf hypertrophy, Gowers sign, and mild waddling gait. His sister was noted to have cardiomegaly on chest x-ray at age 20, but had no symptoms until 27 years of age, when she developed rapidly progressive heart failure during pregnancy; after induced abortion, her cardiac function recovered and she remained asymptomatic. The unaffected parents were each heterozygous for 1 of the mutations, respectively, and the missense mutation was not found in 100 control chromosomes.
In a Japanese brother and sister and 2 unrelated Japanese women with dilated cardiomyopathy (CMD1X; 611615), Murakami et al. (2006) identified compound heterozygosity for 2 mutations in the FKTN gene: the 3-kb retroposon insertion (607440.0001) and a 536G-C transversion resulting in an arg179-to-thr (R179T) substitution at a highly conserved residue. The brother was a swimmer with no muscle weakness or calf hypertrophy. He developed dyspnea at 12 years of age, was diagnosed with cardiomyopathy, and died within a month from heart failure; autopsy revealed severe CMD with lymphocytic infiltration and fibrosis. His 22-year-old sister was diagnosed with cardiomyopathy at 11 years of age and was noted to have calf hypertrophy, but remained asymptomatic with no muscle weakness. The 2 unrelated Japanese women were diagnosed with CMD at ages 46 and 30 years, respectively; the former had mild proximal muscle weakness without facial muscle involvement, and the latter was noted to have proximal muscle weakness with a waddling gait. The unaffected parents of the brother and sister were each heterozygous for 1 of the mutations, respectively, and the missense mutation was not found in 100 control chromosomes.
This variant, formerly titled WALKER-WARBURG SYNDROME, FKTN-RELATED, has been reclassified based on the findings of Bell et al. (2011).
In a Spanish female infant diagnosed with Walker-Warburg syndrome (MDDGA4; 253800), who died at day 5 of life, Cotarelo et al. (2008) identified compound heterozygosity for a 373G-A transition in exon 5 of the FKTN gene, resulting in a gly125-to-ser (G125S) substitution, and a 473-bp deletion in exon 10 of the FKTN gene (607440.0013) that includes the polyadenylation signal. The patient was not a carrier of the founder retrotransposal insertion (607440.0001).
In a preconception carrier screen for 448 severe recessive childhood diseases involving 437 target genes, Bell et al. (2011) found that the G125S mutation in FKTN is a polymorphism carried by unaffected individuals.
For discussion of the 473-bp deletion in exon 10 of the FKTN gene, which included the polyadenylation signal, that was found in compound heterozygous state in a patient diagnosed with Walker-Warburg syndrome (MDDGA4; 253800) by Cotarelo et al. (2008), see 607440.0012.
In 2 brothers of Japanese and Caucasian ancestry with limb-girdle muscular dystrophy (MDDGC4; 611588), Puckett et al. (2009) identified compound heterozygosity for 2 mutations in the FKTN gene: a 340G-A transition in exon 4, resulting in an ala114-to-thr (A114T) substitution, and a 527T-C transition in exon 5, resulting in a phe176-to-ser (F176S; 607440.0015) substitution. The A114T mutation was previously found in 2 sibs with a similar presentation (Godfrey et al., 2007). The F176S mutation, which occurs in a highly conserved residue, was not found in 90 control individuals. The A114T mutation was inherited from the Caucasian father, and the F176S mutation was inherited from the Japanese mother; both parents were unaffected. The phenotype was relatively mild, and there was no cardiac or cognitive involvement. Skeletal muscle biopsy showed defective glycosylation of alpha-dystroglycan.
For discussion of the 527T-C transition in exon 5 of the FKTN gene, resulting in a phe176-to-ser (F176S; 607440.0015) substitution, that was found in compound heterozygous state in 2 brothers of Japanese and Caucasian ancestry with limb-girdle muscular dystrophy (MDDGC4; 611588) by Puckett et al. (2009), see 607440.0014.
In 2 Portuguese sisters with Fukuyama congenital muscular dystrophy (MDDGA4; 253800), Vuillaumier-Barrot et al. (2009) identified compound heterozygosity for 2 mutations in the FKTN gene: 509C-A transversion in exon 5 of the FKTN gene, resulting in an ala170-to-gly (A170E) substitution, and a 1112A-G transition in exon 9, resulting in a tyr371-to-cys (Y371C; 607440.0017) substitution. Both girls had a severe phenotype, with congenital muscular dystrophy, joint contracture, respiratory insufficiency, and mental retardation.
Using human mutant FKTN constructs with expression in mouse myoblasts, Tachikawa et al. (2012) found that the A170E and Y371C mutant proteins showed aberrant accumulation in the endoplasmic reticulum due to protein misfolding and failure of the anterograde pathway, in contrast to wildtype FKTN which localized to the Golgi apparatus. Expression studies in Fktn-null mouse embryonic cells showed that the mutant proteins retained normal glycosylation activity, indicating that these disease-causing mutations are pathogenic due to abnormal folding and localization. Low-temperature culture or treatment with curcumin variably corrected the subcellular localization of the missense mutant proteins.
For discussion of the 1112A-G transition in exon 9 of the FKTN gene, resulting in a tyr371-to-cys (Y371C) substitution, that was found in compound heterozygous state in 2 Portuguese sisters with Fukuyama congenital muscular dystrophy (MDDGA4; 253800) by Vuillaumier-Barrot et al. (2009), see 607440.0016.
In a patient with Walker-Warburg syndrome (MDDGA4; 253800), Godfrey et al. (2007) identified a homozygous 919C-T transition in exon 8 of the FKTN gene, resulting in an arg307-to-ter (R307X) substitution. The patient was 1 of 92 patients with 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.
For discussion of the 1-bp deletion (42delG) in the FKTN gene that was found in compound heterozygous state in a patient with congenital muscular dystrophy-dystroglycanopathy (MDDGB4; 613152) by Mercuri et al. (2009), see 607440.0009.
Bell, C. J., Dinwiddie, D. L., Miller, N. A., Hateley, S. L., Ganusova, E. E., Mudge, J., Langley, R. J., Zhang, L., Lee, C. C., Schilkey, F. D., Sheth, V., Woodward, J. E., Peckham, H. E., Schroth, G. P., Kim, R. W., Kingsmore, S. F. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci. Transl. Med. 3: 65ra4, 2011. Note: Electronic Article. [PubMed: 21228398] [Full Text: https://doi.org/10.1126/scitranslmed.3001756]
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