Structural organization, complete genomic sequences and mutational analyses of the Fukuyama‐type congenital muscular dystrophy gene, <i>fukutin</i>

Kobayashi, Kenzo; Sasaki, Junko; Kondo-Iida, Eri; Fukuda, Yoshimasa; Kinoshita, Moritoshi; Sunada, Yoshihide; Nakamura, Yusuke; Toda, Tatsushi

doi:10.1016/s0014-5793(01)02088-9

Cited by 40 publications

(26 citation statements)

References 16 publications

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“…A retrotransposon insertion into the 3′ untranslated region of FKTN, the Japanese founder mutation, has now been shown to cause a splicing defect resulting in truncation of the C terminus and addition of exogenous sequence that results in mislocalization to the ER (63). Penetrance of the FKTN splicing defect was variable in patient lymphoblasts, and multiple alternatively spliced FKTN mRNA human variants have been reported previously (63,64). Therefore, the milder nature and variability of phenotype for patients homozygous for the founder mutation support the idea that differences in regulation of its pathogenic splicing are a possible source of patient variability that could be developmentally regulated.…”

Section: Discussionmentioning

confidence: 99%

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Beedle¹,

Turner²,

Saito³

et al. 2012

J. Clin. Invest.

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Dystroglycan is a transmembrane glycoprotein that links the extracellular basement membrane to cytoplasmic dystrophin. Disruption of the extensive carbohydrate structure normally present on α-dystroglycan causes an array of congenital and limb girdle muscular dystrophies known as dystroglycanopathies. The essential role of dystroglycan in development has hampered elucidation of the mechanisms underlying dystroglycanopathies. Here, we developed a dystroglycanopathy mouse model using inducible or muscle-specific promoters to conditionally disrupt fukutin (Fktn), a gene required for dystroglycan processing. In conditional Fktn-KO mice, we observed a near absence of functionally glycosylated dystroglycan within 18 days of gene deletion. Twentyweek-old KO mice showed clear dystrophic histopathology and a defect in glycosylation near the dystroglycan O-mannose phosphate, whether onset of Fktn excision driven by muscle-specific promoters occurred at E8 or E17. However, the earlier gene deletion resulted in more severe phenotypes, with a faster onset of damage and weakness, reduced weight and viability, and regenerating fibers of smaller size. The dependence of phenotype severity on the developmental timing of muscle Fktn deletion supports a role for dystroglycan in muscle development or differentiation. Moreover, given that this conditional Fktn-KO mouse allows the generation of tissue-and timingspecific defects in dystroglycan glycosylation, avoids embryonic lethality, and produces a phenotype resembling patient pathology, it is a promising new model for the study of secondary dystroglycanopathy.

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Section: Discussionmentioning

confidence: 99%

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Beedle¹,

Turner²,

Saito³

et al. 2012

J. Clin. Invest.

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“…The first gene in the operon, pcgD, encoded a protein which contained a partial LicD domain and showed identity to LicD, following a PSI-BLAST search, and we predict that this gene encodes the PCho transferase that adds the activated PCho to the galactose residues on the VP161 LPS molecule. Interestingly, the pcgD gene product has only limited similarity with any characterized bacterial proteins but shares identity with genes encoding the human fukutin proteins, which are predicted to be involved in glycosylation of neuronal ␣-dystroglycan and are implicated in Fukuyama congenital muscular dystrophy (18,28). It is tempting to speculate that the human fukutin proteins may also have a role in PCho addition to ␣-dystroglycan, although it is possible that the protein domains which show identity are involved solely in sugar-acceptor binding.…”

Section: Discussionmentioning

confidence: 99%

“…PcgA was 41% identical to the choline kinase (LicA) from H. influenzae, PcgB displayed 39% identity to the LicB (putative choline permease) protein from H. influenzae, and PcgC displayed 46% identity to the CTP: phosphocholine cytidylyltransferase (LicC) from H. influenzae. PcgD showed very limited similarity to characterized bacterial proteins but was 29% identical to the human protein encoded by the fukutin gene, which is implicated in Fukuyama-type congenital muscular dystrophy (18). The last gene in the H. influenzae lic operon (LicD) encodes a phosphocholine transferase required for the transfer of the activated phosphocholine to the nascent LPS molecule (21).…”

Section: Identification Of Genes Involved In Pcho Addition To Lpsmentioning

confidence: 99%

Decoration ofPasteurella multocidaLipopolysaccharide with Phosphocholine Is Important for Virulence

et al. 2007

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Phosphocholine (PCho) is an important substituent of surface structures expressed by a number of bacterial pathogens. Its role in virulence has been investigated in several species, in which it has been shown to play a role in bacterial adhesion to mucosal surfaces, in resistance to antimicrobial peptides, or in sensitivity to complement-mediated killing. The lipopolysaccharide (LPS) structure of Pasteurella multocida strain Pm70, whose genome sequence is known, has recently been determined and does not contain PCho. However, LPS structures from the closely related, virulent P. multocida strains VP161 and X-73 were shown to contain PCho on their terminal galactose sugar residues. To determine if PCho was involved in the virulence of P. multocida, we used subtractive hybridization of the VP161 genome against the Pm70 genome to identify a four-gene locus (designated pcgDABC) which we show is required for the addition of the PCho residues to LPS. The proteins predicted to be encoded by pcgABC showed identity to proteins involved in choline uptake, phosphorylation, and nucleotide sugar activation of PCho. We constructed a P. multocida VP161 pcgC mutant and demonstrated that this strain produces LPS that lacks PCho on the terminal galactose residues. This pcgC mutant displayed reduced in vivo growth in a chicken infection model and was more sensitive to the chicken antimicrobial peptide fowlicidin-1 than the wild-type P. multocida strain.

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“…The RϾQ203 SNP has been recently reported by another group (Kobayashi et al 2001). In addition, we have ruled out the presence of coding sequence mutations in the fukutin gene among three subjects with BSCL.…”

Section: Discussionmentioning

confidence: 75%

Single nucleotide polymorphisms of the fukutin gene

2001

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Mutations in the LMNA gene, which encodes nuclear lamins A and C, underlie both Emery-Dreifuss muscular dystrophy (EMD2) and Dunnigan-type familial partial lipodystrophy (FPLD). This indicates that one gene can cause different phenotypes characterized by tissue degeneration. The gene for one form of Berardinelli-Seip-type congenital total lipodystrophy (BSCL) has been mapped to chromosome 9q34. Based on the observation that one gene caused both FPLD and EMD2, we considered that a known gene for muscular dystrophy at or near the BSCL locus on chromosome 9q would be an appropriate candidate for BSCL. The gene encoding fukutin, which is mutated in Fukuyama congenital muscular dystrophy has been mapped to 9q31. We thus developed amplification primers for the coding regions of the fukutin gene. We found no putative disease mutations, but through screening of diseased and normal subjects, we identified three novel single nucleotide polymorphisms (SNPs). We conclude that mutations in fukutin are not present in subjects with BSCL. However, the identification of SNPs provides tools to investigate this protein for association with other phenotypes.

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Structural organization, complete genomic sequences and mutational analyses of the Fukuyama‐type congenital muscular dystrophy gene, fukutin

Cited by 40 publications

References 16 publications

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy

Decoration ofPasteurella multocidaLipopolysaccharide with Phosphocholine Is Important for Virulence

Single nucleotide polymorphisms of the fukutin gene

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