HGNC Approved Gene Symbol: FKRP
SNOMEDCT: 718180000; ICD10CM: G71.038;
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38) : 19:46,744,760-46,758,575 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.32 | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5 | 613153 | Autosomal recessive | 3 |
| Muscular dystrophy-dystroglycanopathy (congenital with or without impaired intellectual development), type B, 5 | 606612 | Autosomal recessive | 3 | |
| Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5 | 607155 | Autosomal recessive | 3 |
Brockington et al. (2001) identified the fukutin-related protein gene (FKRP) by database screening with the mouse fukutin sequence as query. The human version of the sequence was determined by a combination of EST assembly, RT-PCR, and RACE. The cDNA encodes a deduced 495-amino acid protein. Sequence analysis predicted a molecular organization similar to that found in several Golgi-resident glycosyltransferases. Northern blot analysis detected a 4.0-kb FKRP transcript expressed predominantly in skeletal muscle, placenta, and heart, and relatively weakly in other tissues.
Using transfection experiments, Esapa et al. (2002) determined that FKRP and fukutin (FKTN; 607440) are targeted to the medial Golgi apparatus through their N termini and transmembrane domains.
Brockington et al. (2001) determined that the 12-kb FKRP gene is composed of 3 noncoding exons and a single large exon of 3.8 kb that contains part of the 5-prime untranslated region (UTR) and the entire open reading frame (ORF) and 3-prime UTR.
By radiation hybrid analysis, Brockington et al. (2001) localized the FKRP gene to chromosome 19q13.3.
Mutation in the FKRP gene can cause 3 different forms of muscular dystrophy-dystroglycanopathy (MDDG): a severe congenital form with brain and eye anomalies (type A5; MDDGA5; 613153), formerly designated Walker-Warburg syndrome (WWS) or muscle-eye-brain disease (MEB); a less severe congenital form with or without impaired intellectual development (type B5; MDDGB5; 606612); and a milder limb-girdle form (type C5; MDDGC5; 607155), also known as LGMDR9 and LGMD2I.
In 7 families with a distinct form of congenital muscular dystrophy (MDDGB5; 606612), Brockington et al. (2001) identified 11 different mutations in the FKRP gene (see, e.g., 606596.0001-606596.0003). Nine were missense mutations and 2 were nonsense mutations. In 4 families, the affected individuals were compound heterozygotes; in the other 3, the patients were homozygotes.
In 17 of 25 families with limb-girdle muscular dystrophy (MDDGC5; 607155), Brockington et al. (2001) found mutations in the FKRP gene. Affected individuals from 15 of 17 families had an identical L276I mutation (606596.0004); individuals in 5 families were homozygous for this mutation. Linkage analysis identified at least 2 possible haplotypes in linkage disequilibrium with this mutation. Patients with the L276I change had the clinically less severe phenotype, suggesting that this is a less disruptive FKRP mutation than those found in MDDGB5. A variable reduction of alpha-dystroglycan (DAG1; 128239) expression was observed in the skeletal muscle biopsy of all individuals studied. In addition, several cases showed a deficiency of laminin-2 (LAMA2; 156225) either by immunocytochemistry or Western blotting.
Esapa et al. (2002) found that overexpression of FKRP in CHO cells altered the posttranslational processing of alpha- and beta-dystroglycan, thus inhibiting maturation of the 2 isoforms. Mutations in the DxD motif or in the Golgi-targeting sequence, which cause inefficient trafficking of FKRP to the Golgi apparatus, did not alter dystroglycan processing in vitro. The P448L mutation in FKRP (606596.0003) resulted in mislocalization of the mutant protein and disruption in dystroglycan processing. Esapa et al. (2002) concluded that FKRP is required for the posttranslational modification of dystroglycan. They suggested that aberrant processing of dystroglycan caused by a mislocalized FKRP mutant could be a novel mechanism that causes congenital muscular dystrophy.
In 16 patients with LGMD (MDDGC5; 607155) from 13 Brazilian families, de Paula et al. (2003) identified 10 distinct mutations, including 9 novel mutations, in the FKRP gene (see, e.g., 606596.0012-606596.0015). The most common mutation, L276I (606596.0004), was identified in 9 of 26 alleles.
Beltran-Valero de Bernabe et al. (2004) identified homozygous mutations in the FKRP gene (Y307N, 606596.0016 and C318Y, 606596.0017) in 2 unrelated patients with muscle-eye-brain disease and Walker-Warburg syndrome (MDDGA5; 613153), respectively. Both disorders are characterized by severe disruption of brain and eye structure in addition to muscular dystrophy. The findings expanded the phenotypic spectrum of disorders associated with mutation in the FKRP gene.
Mercuri et al. (2009) identified FKRP mutations in 7 (9%) of 81 Italian patients with a dystroglycanopathy. Three had MEB and 4 had a less severe congenital muscular dystrophy. Three patients had normal brain MRI. In general, the more severe phenotypes appeared to be associated with mutations predicted to result in severe disruption of the gene.
In transfected COS-7 cells, Esapa et al. (2005) showed that FKRP mutants, which are associated with the more severe disease phenotypes (S221R, 606596.0008; A455D, 606596.0009; P448L, 606596.0003) were retained in the endoplasmic reticulum (ER), whereas the wildtype protein and the mutant L276I (606596.0004) that causes LGMD (MDDGC5) were found predominantly in the Golgi apparatus. The ER-retained proteins had a shorter half-life than the wildtype FKRP and were preferentially degraded by the proteasome. Furthermore, calnexin (CANX; 114217) bound preferentially to the ER-retained mutants, suggesting that it may participate in the quality control pathway for FKRP.
Sveen et al. (2006) identified FKRP mutations in 38 of 99 Danish individuals with a clinical diagnosis of limb-girdle muscular dystrophy. Of the 38 individuals, 27 were homozygous for L276I, and 11 were compound heterozygous for L276I and another pathogenic FKRP mutation. The homozygous patients had later onset, milder clinical progression, and less muscle weakness compared to compound heterozygous patients, all of whom were wheelchair-bound by their mid-twenties. Cardiac and respiratory involvement was found in both groups. Nine L276I homozygous, but no compound heterozygous, patients had initial symptoms of exertional myoglobinuria. The L276I variant was identified in 1 of 200 control alleles.
In a retrospective review of brain MRI in patients with FKRP mutations, Mercuri et al. (2006) found a range of various patterns. Five of 13 patients had normal imaging results and normal neurologic function. Three patients had isolated cerebellar cysts and mental retardation without other abnormal brain structure. Of the 5 remaining patients, 2 had features of muscle-eye-brain disease, 1 had features of Walker-Warburg syndrome, and 2 had cerebellar cysts with nodular heterotopia and cerebellar dysplasia, respectively. There was no correlation with severity of the neurologic involvement and FKRP mutation. Mercuri et al. (2006) postulated that the variability may be related to the severity of disruption of alpha-dystroglycan glycosylation.
Ackroyd et al. (2009) found that mice with a homozygous knockin Y307N (606596.0016) mutation in the Fkrp showed no distinguishable phenotype from wildtype mice up to 6 months of age. Fkrp transcript levels were similar to controls. However, mice homozygous for the Y307N mutation and a neomycin cassette in intron 2 of the Fkrp gene died soon after birth. These mice showed a reduction of alpha-dystroglycan in muscle, eye and brain, and had reduced levels of Fkrp transcript (about 40% of control values). The phenotype was consistent with muscle-eye-brain disease in humans; mutant mice showed decreased muscle mass, perturbation of the limiting membrane of the eye, and a disturbance in neuronal migration. The results suggested that the generation of a mouse model for FKRP-related muscular dystrophy requires a knockdown hypomorph Fkrp allele rather than a knockin missense mutation in order to give rise to a disease phenotype.
Kawahara et al. (2010) reported that downregulating fkrp expression in zebrafish by 2 different morpholinos resulted in embryos that had developmental defects similar to those observed in human muscular dystrophies associated with human FKRP mutations. The fkrp morphants showed phenotypes involving alterations in somitic structure and muscle fiber organization, as well as defects in developing eye morphology. Additionally, they were found to have a reduction in alpha-dystroglycan (DAG1; 128239) glycosylation and a shortened myofiber length. Coinjection of fish or human FKRP mRNA along with the morpholino restored normal development, alpha-dystroglycan glycosylation, and laminin- binding activity of alpha-dystroglycan in the morphants. Coinjection of the human FKRP mRNA containing mutations causative of human disorders could not significantly restore their phenotypes. Morphant zebrafish harboring human FKRP mutations showed a wide phenotypic range, similar to that seen in humans.
Chan et al. (2010) generated a transgenic mouse model with a P448L Fkrp mutation (606596.0003) and a neomycin cassette. About one-third of homozygous P448L mice died at birth or within 2 days. The remaining mice recapitulated the features of FKRP-associated muscular dystrophy, including muscle weakness, dystrophic pathology in skeletal muscles, increased serum creatine kinase, and eye and brain abnormalities, such as hydrocephalus and abnormal neuronal migration. Biochemical analysis showed that alpha-DAG was not functionally glycosylated. In another mouse model, homozygous deletion of the C-terminal consensus DxD motif (E310del/E310del) resulted in early embryonic lethality. Only a few compound heterozygous mice (P448L/E310del) were born, and they died at birth. The findings confirmed a critical role of FKRP in posttranslational modification of alpha-DAG. In a follow-up to the study of Chan et al. (2010), Blaeser et al. (2013) generated several mouse models carrying different combinations of mutations in the Fkrp gene, including P448L, E310del, and L276I (606596.0004). One surviving mouse that was compound heterozygous for P448L/E310del showed a severe dystrophic phenotype, with muscle degeneration, hydrocephalus, and abnormal migration of neurons in the cerebral cortex and cerebellum. In contrast, most of the L276I/P448L or L276I/E310del compound heterozygous mice were normal, but some showed later onset of mild muscle weakness associated with increased serum creatine kinase and mild muscular dystrophy without brain abnormalities. Skeletal muscle from these mutant mice showed less severe decreases in Fkrp expression and higher amounts of functional glycosylated DAG compared to P448L/E310del, P448L/P448L, and E310del/E310del mice. Removal of the neomycin cassette from the mutant alleles resulted in increased Fkrp levels and attenuated the phenotypes in all mutants. The findings indicated that L276I can provide sufficient activity to avoid neurologic defects, suggesting that different missense mutations affect the function of FKRP, resulting in phenotypic variability. The wide range of disease phenotypes observed in these mice recapitulated the variable phenotypic severity observed in humans with different FKRP mutations.
Mercuri et al. (2000) described the clinical features of 2 sibs in a Scottish family who appeared to be affected by a novel form of congenital muscular dystrophy (MDDGB5; 606612). Both children presented soon after birth with hypotonia and feeding difficulties. They never acquired the ability to walk because of severe weakness, which also affected their facial muscles. Weakness was greater in the arms than legs, with prominent wasting of the deltoids and pectoral muscles, whereas both calf and quadriceps muscles were hypertrophied. Cognitive development, intelligence, and vision were normal, as was brain MRI. Serum creatine kinase was markedly elevated. The older sib died suddenly at age 7 years, following an upper respiratory tract infection. Brockington et al. (2001) found that these affected sibs were compound heterozygotes for mutations in the FKRP gene: tyr309-to-cys (Y309C) and ser385-to-ter (S385X; 606596.0002).
For discussion of the ser385-to-ter (S385X) mutation in the FKRP gene that was found in compound heterozygous state in patients with a form of congenital muscular dystrophy (MDDGB5; 606612) by Brockington et al. (2001), see 606596.0001.
In a consanguineous family from Libya with a severe form of congenital muscular dystrophy (MDDGB5; 606612), Brockington et al. (2001) found that the 1 affected child was homozygous for a pro448-to-leu (P448L) missense mutation in the FKRP gene. The patient presented in the first few weeks of life with hypotonia and feeding difficulties, followed by motor delay. On examination at age 16 months, she could not walk and was weaker in her arms than in her legs. She had calf hypertrophy and facial weakness. Serum creatine kinase was very high, and she had a myopathic EMG. Her intelligence was normal.
In 15 of 17 families with autosomal recessive limb-girdle muscular dystrophy (MDDGC5; 607155), Brockington et al. (2001) found homozygosity or compound heterozygosity for an 826C-A transversion in the FKRP gene, predicted to result in a substitution of isoleucine for leucine 276 (L276I). Patients with the L276I change had the clinically less severe phenotype, suggesting that this is a less disruptive FKRP mutation than those found in patients with MDDGB5; see, e.g., 606596.0001.
Mercuri et al. (2003) reported a patient with limb-girdle muscular dystrophy who was compound heterozygous for 2 mutations in the FKRP gene: L276I and Y307N (606596.0016). The patient had an unusually severe form of the disorder and died in his early teens.
De Paula et al. (2003) identified the L276I mutation in 9 of 26 mutated alleles among 13 Brazilian families with LGMD (MDDGC5).
In affected members of 5 Hutterite families with autosomal recessive LGMD, Frosk et al. (2005) identified homozygosity for the L276I mutation. A single common haplotype surrounding the FKRP gene was identified in the Hutterite LGMD patients, and an identical core haplotype was also found in 19 other non-Hutterite LGMD patients from Europe, Canada, and Brazil, carrying the L276I mutation. This finding indicated that the L276I dispersed from populations of European origin.
Frosk et al. (2005) reported a Hutterite family in which 2 boys, aged 7 and 10 years, were homozygous for both the L276I mutation and an LGMD2H (LGMDR8; 254110)-related TRIM32 mutation (D487N; 602290.0001). Although they presented at an early age with exercise intolerance and increased serum creatine kinase, the clinical phenotype was not significantly more severe than that of patients with isolated disease. Both parents and 3 other sibs were carriers of the L276I mutation and homozygous for the D487N mutation, with highly variable phenotypic expression.
Sveen et al. (2006) identified the L276I mutation in 38 Danish patients with LGMD, of whom 27 were homozygous, and 11 were compound heterozygous with another pathogenic FKRP mutation. The variant was detected in 1 of 200 control alleles.
Among 1,127 Schmiedeleut (S-leut) Hutterites from the United States, Chong et al. (2012) found 121 heterozygotes and 3 homozygotes for the L276I mutation in the FKRP gene, for a frequency of 0.107, or 1 in 9.5. The carrier frequency in other populations is 1 in 300 (Frosk et al., 2005).
In an individual with early-onset limb-girdle muscular dystrophy (MDDGC5; 607155), Brockington et al. (2001), described compound heterozygosity for mutations in the FKRP gene. One allele contained the recurrent L276I mutation (606596.0004), whereas the other allele harbored a 4-bp insertion TACC (390insTACC), which is predicted to generate a premature stop codon at the position of gly132.
In a consanguineous Tunisian family in which 13 members had limb-girdle muscular dystrophy (MDDGC5; 607155), Driss et al. (2003) identified a homozygous 1486T-A change in the FKRP gene, which abolishes a stop codon and is predicted to add 21 amino acids to the C-terminal end of the protein. The patients had symmetric proximal muscle weakness and wasting in all 4 limbs. No heart involvement was found. Immunohistochemical and immunoblot analysis showed abnormal expression of alpha-dystroglycan and alpha-2 laminin, supporting the hypothesis that FKRP has a role in the interaction between components of the extracellular matrix.
In a patient with severe merosin-deficient congenital muscular dystrophy (MDDGB5; 606612) reported by Talim et al. (2000), Topaloglu et al. (2003) identified a homozygous 946C-A transversion in the FKRP gene, resulting in a pro316-to-thr (P316T) substitution. The patient was from a consanguineous family, and showed hypotonia, muscle weakness, a myopathic face, and high-arched palate by age 1.5 years. She also had lordosis and scoliosis, and was never able to stand or walk. In addition, she had mild mental retardation and multiple small cysts in the cerebellar cortical and subcortical areas of the brain. Also see 606596.0008.
In a patient with congenital muscular dystrophy (MDDGB5; 606612), Topaloglu et al. (2003) identified a homozygous 663C-A transversion in the FKRP gene, resulting in a ser221-to-arg (S221R) substitution. In addition to the characteristic features of weakness, hypotonia, dystrophic muscle biopsy, and inability to walk, the patient also had mild mental retardation and cerebellar cysts. The authors noted that mental retardation and structural brain changes are not usually part of the clinical spectrum of patients with FKRP mutations, and that these findings may expand the phenotypic spectrum. Also see 606596.0007.
In 6 unrelated Tunisian patients with congenital muscular dystrophy (MDDGB5; 606612), previously designated MDC1C, Louhichi et al. (2004) identified a homozygous 1364C-A transversion in the FKRP gene, resulting in an ala455-to-asp (A455D) substitution. All patients came from unrelated consanguineous families. Microsatellite marker analysis suggested a founder effect. In addition to a typical MDC1C phenotype, the patients also had severe psychomotor retardation, mental retardation, and white matter changes and/or cerebellar structural abnormalities on MRI. Louhichi et al. (2004) noted the similarities to the patients reported by Topaloglu et al. (2003) (see 606596.0007-606596.0008).
In an Algerian patient with congenital muscular dystrophy (MDDGB5; 606612) born of consanguineous parents, Louhichi et al. (2004) identified a homozygous 1213G-T transversion in the FKRP gene, resulting in a val405-to-leu (V405L) substitution. The patient also had mental retardation, white matter changes on MRI, and cerebellar cysts.
In 8 affected members of a large consanguineous Bedouin family with limb-girdle muscular dystrophy (MDDGC5; 607155), Harel et al. (2004) identified a homozygous 160C-T transition in exon 4 of the FKRP gene, resulting in an arg54-to-trp (R54W) substitution.
In 3 Brazilian sisters with a severe form of LGMD (MDDGC5; 607155), de Paula et al. (2003) identified compound heterozygosity for 2 mutations in the FKRP gene: a 235G-A transition, resulting in a val79-to-met (V79M) substitution, and a 764G-A transition, resulting in a trp255-to-ter (W255X; 606596.0013) substitution. All 3 patients showed hypotonia at birth; 2 were confined to wheelchairs at ages 11 and 12 years and died of cardiorespiratory failure at ages 14 and 15 years, respectively. Neither mutation was identified in 200 control chromosomes.
For discussion of the 764G-A transition in the FKRP gene, resulting in a trp255-to-ter (W255X; 606596.0013) substitution, that was found in compound heterozygous state in Brazilian patients with a severe form of LGMD (MDDGC5; 607155) by de Paula et al. (2003), see 606596.0012.
In 2 Brazilian sibs, from a consanguineous family, with LGMD (MDDGC5; 607155), de Paula et al. (2003) identified a homozygous 400C-T transition in the FKRP gene, resulting in an arg134-to-trp (R134W) substitution. Ages at onset were 26 and 19 years, respectively. Two clinically unaffected sibs also carried the homozygous R134W mutation; although clinical examination was normal at ages 22 and 31 years, respectively, both had increased serum creatine kinase. The mutation was not identified in 200 control chromosomes.
In a Brazilian woman, from a consanguineous family, with LGMD (MDDGC5; 607155), de Paula et al. (2003) identified a homozygous 899T-C transition in the FKRP gene, resulting in a val300-to-ala (V300A) substitution. She had onset at age 14 years and died from pneumonia at age 33 years. Two clinically unaffected sibs also carried the homozygous V300A mutation; although clinical examination was normal at ages 31 and 29 years, respectively, both had increased serum creatine kinase. The mutation was not identified in 200 control chromosomes.
In a patient with muscle-eye-brain disease (MDDGA5; 613153), Beltran-Valero de Bernabe et al. (2004) identified a homozygous 919T-A transversion in the FKRP gene, resulting in a tyr307-to-asn (Y307N) substitution in the catalytic domain of the protein. The mutation was not identified in 200 controls.
Mercuri et al. (2003) reported a patient with LGMD (MDDGC5; 607155) who was compound heterozygous for 2 mutations in the FKRP gene: L276I (606596.0004) and Y307N. The patient had an unusually severe form of the disorder and died in his early teens.
In a patient with Walker-Warburg syndrome (MDDGA5; 613153), Beltran-Valero de Bernabe et al. (2004) identified a homozygous 953G-A transition in the FKRP gene, resulting in a cys318-to-tyr (C318Y) substitution in the catalytic domain of the protein. The mutation was not identified in 200 controls.
In 2 unrelated girls of Mexican descent with congenital muscular dystrophy (MDDGB5; 606612), MacLeod et al. (2007) identified a homozygous 1387A-G transition in the FKRP gene, resulting in an asn463-to-asp (N463D) substitution near the C terminus. Both girls had onset of muscle weakness from birth without neurologic or cardiac abnormalities. Skeletal muscle biopsies showed chronic myopathic changes with decreased immunoreactivity for alpha- and beta-dystroglycan (DAG1; 128239) as well as several sarcoglycans (see, e.g., SGCA; 600119), suggesting that multiple members of the membrane glycoprotein complex were affected.
In 2 sibs, the offspring of consanguineous parents, with a clinical diagnosis of Walker-Warburg syndrome (MDDGA5; 613153), van Reeuwijk et al. (2010) identified a homozygous c.1A-G transition in the FKRP gene, resulting in a met1-to-val (M1V) substitution in the start codon, predicted to result in a complete loss of protein function. The mutation was found by homozygosity mapping combined with candidate gene sequencing. The unaffected parents were heterozygous for the mutation. The first child was born with severe hydrocephalus and showed limited spontaneous movements. He had microphthalmia, asymmetric pupils, absent pupillary light reflexes, and cataracts. Brain MRI showed aqueductal stenosis and small cerebellum and pons with kinking of the brainstem. Muscle biopsy showed muscular dystrophy. The infant died of respiratory distress at 6 days of age. Severe hydrocephalus was diagnosed at about 17 weeks' gestation in a subsequent pregnancy, and the pregnancy was terminated. Autopsy was not performed. Van Reeuwijk et al. (2010) predicted that the M1V mutation would result in a null allele, which correlated with the severe phenotype seen in these sibs.
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