* 604973

FICOLIN 3; FCN3


Alternative titles; symbols

HAKATA ANTIGEN; HAKA1
COLLAGEN/FIBRINOGEN DOMAIN-CONTAINING LECTIN 3 P35


HGNC Approved Gene Symbol: FCN3

Cytogenetic location: 1p36.11     Genomic coordinates (GRCh38): 1:27,369,110-27,374,824 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p36.11 Immunodeficiency due to ficolin 3 deficiency 613860 AR 3

TEXT

Description

Ficolin-3, also known as the Hakata antigen, is a recognition molecule in the lectin pathway of the complement system. It is the predominant lectin-pathway recognition molecule in plasma (summary by Munthe-Fog et al., 2009).


Cloning and Expression

Based on micropeptide sequence analysis and the use of PCR to screen a lung cDNA library, Sugimoto et al. (1998) obtained a cDNA encoding the Hakata antigen, which was later designated ficolin-3 (FCN3). Sequence analysis predicted that the deduced 299-amino acid protein contains a 24-amino acid signal sequence, 1 potential N-glycosylation site, a collagen-like domain, and a fibrinogen-like domain. The Hakata antigen shows 48% sequence homology with the FCN1 (601252) and FCN2 (601624) proteins. Western blot analysis demonstrated that the Hakata antigen is expressed as a 35-kD protein that reacts with systemic lupus erythematosus (SLE; 125270) sera. Electron microscopy showed that the Hakata antigen resembles FCN1, having globular domains on the ends of thin rods.


Mapping

Gross (2013) mapped the FCN3 gene to chromosome 1p36.11 based on an alignment of the FCN3 sequence (GenBank AY756173) with the genomic sequence (GRCh37).


Biochemical Features

Using sandwich ELISA, Jarlhelt et al. (2020) showed that ficolin-2 and ficolin-3 interact and are present as a heterocomplex, which they named the ficolin-23 complex, in normal human serum and plasma. Purified recombinant ficolin-2 and ficolin-3 did not form complexes when mixed, but formed complexes when coexpressed in CHO cells. Western blot analysis suggested that the ficolin-23 complex was likely formed through disulfide bonds between ficolin-2 and ficolin-3. Size-exclusion chromatography found that the heterocomplex is a mixture of different oligomeric forms. In human plasma, the mean concentration was determined to be 4.15 microg/ml for ficolin 2, 27.41 microg/ml for ficolin 3, and 97.86 arbitrary units (AU)/ml for the ficolin-23 complex. The concentration of the ficolin-23 heterocomplex correlated significantly with the concentrations of ficolin-2 and ficolin-3.


Gene Function

Unlike FCN1 and FCN2, Hakata antigen does not bind fibronectin (FN1; 135600), elastin (ELN; 130160), or zymosan. Like FCN1, the lectin activity of the Hakata antigen is calcium independent (Sugimoto et al., 1998).

The Hakata antigen is a thermolabile beta-2-macroglycoprotein found in all human serum. Antibody to this antigen is found 14 times more frequently in the serum of patients with systemic lupus erythematosus (SLE; 152700) than in patients with other autoimmune diseases (Inaba et al., 1990).

Michalski et al. (2015) reported that human FCN3 agglutinated Hafnia alvei, a gram-negative enteric commensal bacterium and opportunistic pathogen, in the presence of calcium. FCN3 also augmented phagocytosis of H. alvei by macrophages and inhibited LPS-dependent cell activation. Michalski et al. (2015) concluded that FCN3 has protective activity against a bacterium that may shift from an intestinal commensal state to an extraintestinal pathogenic state.


Molecular Genetics

In a man with immunodeficiency and recurrent infections associated with complete ficolin-3 deficiency (613860), Munthe-Fog et al. (2009) found homozygosity for a truncating variant in the FCN3 gene (c.1637delC; 604973.0001). He had normal levels of lymphocytes, normal T-cell responses, and normal antibodies, but a selective deficient antibody response to pneumococcal polysaccharide vaccine. Laboratory studies showed impaired complement deposition when acetylated bovine serum albumin was used, indicating a defect in complement activation. The allele frequency of the variant was 0.01 among a total of 1,282 patients with various immunodeficiencies; all were heterozygous for the variant except the index patient. Munthe-Fog et al. (2009) concluded that homozygosity for this variant in the FCN3 gene results in a recessive complement deficiency syndrome.

The 4 unrelated patients with complete FCN3 deficiency reported by Schlapbach et al. (2011), Michalski et al. (2012), and Michalski et al. (2015) were homozygous for the same c.1637delC mutation reported by Munthe-Fog et al. (2009).


Evolution

Endo et al. (2012) noted that human FCN1 is the ortholog of mouse Fcnb. Human FCN2 is closely related to mouse Fcna, but the genes appear to have evolved independently in each murine and primate lineage. The human FCN3 gene is a pseudogene in mouse.


ALLELIC VARIANTS ( 1 Selected Example):

.0001 FICOLIN 3 DEFICIENCY

FCN3, 1-BP DEL, 1637C (rs28357092)
  
RCV000005603

In a man with immunodeficiency and recurrent infections since childhood, associated with ficolin-3 deficiency (613860), Munthe-Fog et al. (2009) identified homozygosity for a 1-bp deletion (1637delC; rs28357092) in exon 5 of the FCN3 gene, resulting in a frameshift and premature termination. Other features included brain abscesses and recurrent warts on the fingers. He had normal levels of lymphocytes, normal T-cell responses, and normal antibodies, but a selective deficient antibody response to pneumococcal polysaccharide vaccine. Laboratory studies showed impaired complement deposition when acetylated bovine serum albumin was used, indicating a defect in complement activation. The patient was born of Macedonian and Albanian parents, each of whom was unaffected and heterozygous for the variant. The allele frequency of the variant was 0.01 among a total of 1,282 patients with various immunodeficiencies; all were heterozygous for the variant except the index patient.

Schlapbach et al. (2011) reported a premature infant with necrotizing enterocolitis who was homozygous for the c.1637delC polymorphism. He had severe FCN3 deficiency, and his parents, who were heterozygous for the polymorphism, had about 50% FCN3 levels compared to controls.

Michalski et al. (2012) reported a male infant born at 35 weeks' gestation who developed infection with Streptococcus agalactiae. Laboratory studies showed complete H-ficolin deficiency as well as low MBL, undetectable MASP2, and low L-ficolin (FCN2; 601624). He had no severe infections during a 5-year follow-up, but he did have microcephaly, poor growth, and mental retardation. The patient was homozygous for the common FCN3 truncating polymorphism.

Michalski et al. (2015) reported 2 unrelated patients with ficolin-3 deficiency due to homozygosity for the c.1637delC variant. One was a 50-year-old man with nephrotic syndrome due to membranous nephropathy. The other patient was an 11-month-old boy who had pneumonia before surgery to repair a cardiac ventricular septal defect. Michalski et al. (2015) concluded that the consequences of FCN3 deficiency are not clear-cut, and suggested that it may act as a disease modifier.

Michalski et al. (2012) evaluated serum H-ficolin levels in 613 neonates, and FNC3 genotypes in 529 neonates; all were of Polish descent. Genotype analysis revealed that 96% were homozygous wildtype, 3.8% were compound heterozygous, and 0.2% (1 infant) was homozygous for the variant allele. The protein was undetectable in the homozygous infant. Preterm delivery and low birthweight were significantly associated with low serum H-ficolin, but not with heterozygosity for the c.1637delC allele, even though the variant allele influenced the protein level. There was no association between heterozygosity for the allele and perinatal infections. Michalski et al. (2012) concluded that heterozygosity for the FCN3 variant does not seem to have major clinical importance.


REFERENCES

  1. Endo, Y., Takahashi, M., Iwaki, D., Ishida, Y., Nakazawa, N., Kodama, T., Matsuzaka, T., Kanno, K., Liu, Y., Tsuchiya, K., Kawamura, I., Ikawa, M., Waguri, S., Wada, I., Matsushita, M., Schwaeble, W. J., Fujita, T. Mice deficient in ficolin, a lectin component pathway recognition molecule, are susceptible to Streptococcus pneumoniae infection. J. Immun. 189: 5860-5866, 2012. [PubMed: 23150716, related citations] [Full Text]

  2. Gross, M. B. Personal Communication. Baltimore, Md. 6/20/2013.

  3. Inaba, S., Okochi, K., Yae, Y., Niklasson, F., de Verder, C.-H. Serological studies of an SLE-associated antigen-antibody system discovered as a precipitation reaction in agarose gel: the Hakata antigen-antibody system. Fukuoka Igaku Zasshi 81: 284-291, 1990. [PubMed: 2276712, related citations]

  4. Jarlhelt, I., Pilely, K., Clausen, J. B., Skjoedt, M.-O., Bayarri-Olmos, R., Garred, P. Circulating ficolin-2 and ficolin-3 form heterocomplexes. J. Immun. 204: 1919-1928, 2020. [PubMed: 32094208, related citations] [Full Text]

  5. Michalski, M., St. Swierzko, A., Lukasiewicz, J., Man-Kupisinska, A., Karwaciak, I., Przygodzka, P., Cedzynski, M. Ficolin-3 activity towards the opportunistic pathogen, Hafnia alvei. Immunobiology 220: 117-123, 2015. [PubMed: 25178935, related citations] [Full Text]

  6. Michalski, M., St. Swierzko, A., Pagowska-Klimek, I., Niemir, Z. I., Mazerant, K., Domzalska-Popadiuk, I., Moll, M., Cedzynski, M. Primary ficolin-3 deficiency--is it associated with increased susceptibility to infections? (Letter) Immunobiology 220: 711-713, 2015. [PubMed: 25662573, related citations] [Full Text]

  7. Michalski, M., Szala, A., St. Swierzko, A., Lukasiewicz, J., Maciejewska, A., Kilpatrick, D. C., Matsushita, M., Domzalska-Popadiuk, I., Borkowska-Klos, M., Sokolowska, A., Szczapa, J., Lugowski, C., Cedzynski, M. H-ficolin (ficolin-3) concentrations and FCN3 gene polymorphism in neonates. Immunobiology 217: 730-737, 2012. [PubMed: 22226667, related citations] [Full Text]

  8. Munthe-Fog, L., Hummelshoj, T., Honore, C., Madsen, H. O., Permin, H., Garred, P. Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency. New Eng. J. Med. 360: 2637-2644, 2009. [PubMed: 19535802, related citations] [Full Text]

  9. Schlapbach, L. J., Thiel, S., Kessler, U., Ammann, R. A., Aebi, C., Jensenius, J. C. Congenital H-ficolin deficiency in premature infants with severe necrotising enterocolitis. (Letter) Gut 60: 1438-1439, 2011. [PubMed: 20971976, related citations] [Full Text]

  10. Sugimoto, R., Yae, Y., Akaiwa, M., Kitajima, S., Shibata, Y., Sato, H., Hirata, J., Okochi, K., Izuhara, K., Hamasaki, N. Cloning and characterization of the Hakata antigen, a member of the ficolin/opsonin p35 lectin family. J. Biol. Chem. 273: 20721-20727, 1998. [PubMed: 9694814, related citations] [Full Text]


Bao Lige - updated : 03/31/2022
Paul J. Converse - updated : 06/06/2016
Cassandra L. Kniffin - updated : 6/2/2016
Matthew B. Gross - updated : 6/20/2013
Cassandra L. Kniffin - updated : 7/8/2009
Creation Date:
Paul J. Converse : 5/17/2000
alopez : 03/31/2022
carol : 10/03/2016
mgross : 06/06/2016
carol : 6/2/2016
ckniffin : 6/2/2016
carol : 5/25/2016
carol : 9/16/2013
mgross : 6/20/2013
carol : 4/4/2011
carol : 7/9/2009
ckniffin : 7/8/2009
carol : 8/4/2000
carol : 5/17/2000

* 604973

FICOLIN 3; FCN3


Alternative titles; symbols

HAKATA ANTIGEN; HAKA1
COLLAGEN/FIBRINOGEN DOMAIN-CONTAINING LECTIN 3 P35


HGNC Approved Gene Symbol: FCN3

Cytogenetic location: 1p36.11     Genomic coordinates (GRCh38): 1:27,369,110-27,374,824 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
1p36.11 Immunodeficiency due to ficolin 3 deficiency 613860 Autosomal recessive 3

TEXT

Description

Ficolin-3, also known as the Hakata antigen, is a recognition molecule in the lectin pathway of the complement system. It is the predominant lectin-pathway recognition molecule in plasma (summary by Munthe-Fog et al., 2009).


Cloning and Expression

Based on micropeptide sequence analysis and the use of PCR to screen a lung cDNA library, Sugimoto et al. (1998) obtained a cDNA encoding the Hakata antigen, which was later designated ficolin-3 (FCN3). Sequence analysis predicted that the deduced 299-amino acid protein contains a 24-amino acid signal sequence, 1 potential N-glycosylation site, a collagen-like domain, and a fibrinogen-like domain. The Hakata antigen shows 48% sequence homology with the FCN1 (601252) and FCN2 (601624) proteins. Western blot analysis demonstrated that the Hakata antigen is expressed as a 35-kD protein that reacts with systemic lupus erythematosus (SLE; 125270) sera. Electron microscopy showed that the Hakata antigen resembles FCN1, having globular domains on the ends of thin rods.


Mapping

Gross (2013) mapped the FCN3 gene to chromosome 1p36.11 based on an alignment of the FCN3 sequence (GenBank AY756173) with the genomic sequence (GRCh37).


Biochemical Features

Using sandwich ELISA, Jarlhelt et al. (2020) showed that ficolin-2 and ficolin-3 interact and are present as a heterocomplex, which they named the ficolin-23 complex, in normal human serum and plasma. Purified recombinant ficolin-2 and ficolin-3 did not form complexes when mixed, but formed complexes when coexpressed in CHO cells. Western blot analysis suggested that the ficolin-23 complex was likely formed through disulfide bonds between ficolin-2 and ficolin-3. Size-exclusion chromatography found that the heterocomplex is a mixture of different oligomeric forms. In human plasma, the mean concentration was determined to be 4.15 microg/ml for ficolin 2, 27.41 microg/ml for ficolin 3, and 97.86 arbitrary units (AU)/ml for the ficolin-23 complex. The concentration of the ficolin-23 heterocomplex correlated significantly with the concentrations of ficolin-2 and ficolin-3.


Gene Function

Unlike FCN1 and FCN2, Hakata antigen does not bind fibronectin (FN1; 135600), elastin (ELN; 130160), or zymosan. Like FCN1, the lectin activity of the Hakata antigen is calcium independent (Sugimoto et al., 1998).

The Hakata antigen is a thermolabile beta-2-macroglycoprotein found in all human serum. Antibody to this antigen is found 14 times more frequently in the serum of patients with systemic lupus erythematosus (SLE; 152700) than in patients with other autoimmune diseases (Inaba et al., 1990).

Michalski et al. (2015) reported that human FCN3 agglutinated Hafnia alvei, a gram-negative enteric commensal bacterium and opportunistic pathogen, in the presence of calcium. FCN3 also augmented phagocytosis of H. alvei by macrophages and inhibited LPS-dependent cell activation. Michalski et al. (2015) concluded that FCN3 has protective activity against a bacterium that may shift from an intestinal commensal state to an extraintestinal pathogenic state.


Molecular Genetics

In a man with immunodeficiency and recurrent infections associated with complete ficolin-3 deficiency (613860), Munthe-Fog et al. (2009) found homozygosity for a truncating variant in the FCN3 gene (c.1637delC; 604973.0001). He had normal levels of lymphocytes, normal T-cell responses, and normal antibodies, but a selective deficient antibody response to pneumococcal polysaccharide vaccine. Laboratory studies showed impaired complement deposition when acetylated bovine serum albumin was used, indicating a defect in complement activation. The allele frequency of the variant was 0.01 among a total of 1,282 patients with various immunodeficiencies; all were heterozygous for the variant except the index patient. Munthe-Fog et al. (2009) concluded that homozygosity for this variant in the FCN3 gene results in a recessive complement deficiency syndrome.

The 4 unrelated patients with complete FCN3 deficiency reported by Schlapbach et al. (2011), Michalski et al. (2012), and Michalski et al. (2015) were homozygous for the same c.1637delC mutation reported by Munthe-Fog et al. (2009).


Evolution

Endo et al. (2012) noted that human FCN1 is the ortholog of mouse Fcnb. Human FCN2 is closely related to mouse Fcna, but the genes appear to have evolved independently in each murine and primate lineage. The human FCN3 gene is a pseudogene in mouse.


ALLELIC VARIANTS 1 Selected Example):

.0001   FICOLIN 3 DEFICIENCY

FCN3, 1-BP DEL, 1637C ({dbSNP rs28357092})
SNP: rs532781899, gnomAD: rs532781899, ClinVar: RCV000005603

In a man with immunodeficiency and recurrent infections since childhood, associated with ficolin-3 deficiency (613860), Munthe-Fog et al. (2009) identified homozygosity for a 1-bp deletion (1637delC; rs28357092) in exon 5 of the FCN3 gene, resulting in a frameshift and premature termination. Other features included brain abscesses and recurrent warts on the fingers. He had normal levels of lymphocytes, normal T-cell responses, and normal antibodies, but a selective deficient antibody response to pneumococcal polysaccharide vaccine. Laboratory studies showed impaired complement deposition when acetylated bovine serum albumin was used, indicating a defect in complement activation. The patient was born of Macedonian and Albanian parents, each of whom was unaffected and heterozygous for the variant. The allele frequency of the variant was 0.01 among a total of 1,282 patients with various immunodeficiencies; all were heterozygous for the variant except the index patient.

Schlapbach et al. (2011) reported a premature infant with necrotizing enterocolitis who was homozygous for the c.1637delC polymorphism. He had severe FCN3 deficiency, and his parents, who were heterozygous for the polymorphism, had about 50% FCN3 levels compared to controls.

Michalski et al. (2012) reported a male infant born at 35 weeks' gestation who developed infection with Streptococcus agalactiae. Laboratory studies showed complete H-ficolin deficiency as well as low MBL, undetectable MASP2, and low L-ficolin (FCN2; 601624). He had no severe infections during a 5-year follow-up, but he did have microcephaly, poor growth, and mental retardation. The patient was homozygous for the common FCN3 truncating polymorphism.

Michalski et al. (2015) reported 2 unrelated patients with ficolin-3 deficiency due to homozygosity for the c.1637delC variant. One was a 50-year-old man with nephrotic syndrome due to membranous nephropathy. The other patient was an 11-month-old boy who had pneumonia before surgery to repair a cardiac ventricular septal defect. Michalski et al. (2015) concluded that the consequences of FCN3 deficiency are not clear-cut, and suggested that it may act as a disease modifier.

Michalski et al. (2012) evaluated serum H-ficolin levels in 613 neonates, and FNC3 genotypes in 529 neonates; all were of Polish descent. Genotype analysis revealed that 96% were homozygous wildtype, 3.8% were compound heterozygous, and 0.2% (1 infant) was homozygous for the variant allele. The protein was undetectable in the homozygous infant. Preterm delivery and low birthweight were significantly associated with low serum H-ficolin, but not with heterozygosity for the c.1637delC allele, even though the variant allele influenced the protein level. There was no association between heterozygosity for the allele and perinatal infections. Michalski et al. (2012) concluded that heterozygosity for the FCN3 variant does not seem to have major clinical importance.


REFERENCES

  1. Endo, Y., Takahashi, M., Iwaki, D., Ishida, Y., Nakazawa, N., Kodama, T., Matsuzaka, T., Kanno, K., Liu, Y., Tsuchiya, K., Kawamura, I., Ikawa, M., Waguri, S., Wada, I., Matsushita, M., Schwaeble, W. J., Fujita, T. Mice deficient in ficolin, a lectin component pathway recognition molecule, are susceptible to Streptococcus pneumoniae infection. J. Immun. 189: 5860-5866, 2012. [PubMed: 23150716] [Full Text: https://doi.org/10.4049/jimmunol.1200836]

  2. Gross, M. B. Personal Communication. Baltimore, Md. 6/20/2013.

  3. Inaba, S., Okochi, K., Yae, Y., Niklasson, F., de Verder, C.-H. Serological studies of an SLE-associated antigen-antibody system discovered as a precipitation reaction in agarose gel: the Hakata antigen-antibody system. Fukuoka Igaku Zasshi 81: 284-291, 1990. [PubMed: 2276712]

  4. Jarlhelt, I., Pilely, K., Clausen, J. B., Skjoedt, M.-O., Bayarri-Olmos, R., Garred, P. Circulating ficolin-2 and ficolin-3 form heterocomplexes. J. Immun. 204: 1919-1928, 2020. [PubMed: 32094208] [Full Text: https://doi.org/10.4049/jimmunol.1900694]

  5. Michalski, M., St. Swierzko, A., Lukasiewicz, J., Man-Kupisinska, A., Karwaciak, I., Przygodzka, P., Cedzynski, M. Ficolin-3 activity towards the opportunistic pathogen, Hafnia alvei. Immunobiology 220: 117-123, 2015. [PubMed: 25178935] [Full Text: https://doi.org/10.1016/j.imbio.2014.08.012]

  6. Michalski, M., St. Swierzko, A., Pagowska-Klimek, I., Niemir, Z. I., Mazerant, K., Domzalska-Popadiuk, I., Moll, M., Cedzynski, M. Primary ficolin-3 deficiency--is it associated with increased susceptibility to infections? (Letter) Immunobiology 220: 711-713, 2015. [PubMed: 25662573] [Full Text: https://doi.org/10.1016/j.imbio.2015.01.003]

  7. Michalski, M., Szala, A., St. Swierzko, A., Lukasiewicz, J., Maciejewska, A., Kilpatrick, D. C., Matsushita, M., Domzalska-Popadiuk, I., Borkowska-Klos, M., Sokolowska, A., Szczapa, J., Lugowski, C., Cedzynski, M. H-ficolin (ficolin-3) concentrations and FCN3 gene polymorphism in neonates. Immunobiology 217: 730-737, 2012. [PubMed: 22226667] [Full Text: https://doi.org/10.1016/j.imbio.2011.12.004]

  8. Munthe-Fog, L., Hummelshoj, T., Honore, C., Madsen, H. O., Permin, H., Garred, P. Immunodeficiency associated with FCN3 mutation and ficolin-3 deficiency. New Eng. J. Med. 360: 2637-2644, 2009. [PubMed: 19535802] [Full Text: https://doi.org/10.1056/NEJMoa0900381]

  9. Schlapbach, L. J., Thiel, S., Kessler, U., Ammann, R. A., Aebi, C., Jensenius, J. C. Congenital H-ficolin deficiency in premature infants with severe necrotising enterocolitis. (Letter) Gut 60: 1438-1439, 2011. [PubMed: 20971976] [Full Text: https://doi.org/10.1136/gut.2010.226027]

  10. Sugimoto, R., Yae, Y., Akaiwa, M., Kitajima, S., Shibata, Y., Sato, H., Hirata, J., Okochi, K., Izuhara, K., Hamasaki, N. Cloning and characterization of the Hakata antigen, a member of the ficolin/opsonin p35 lectin family. J. Biol. Chem. 273: 20721-20727, 1998. [PubMed: 9694814] [Full Text: https://doi.org/10.1074/jbc.273.33.20721]


Contributors:
Bao Lige - updated : 03/31/2022
Paul J. Converse - updated : 06/06/2016
Cassandra L. Kniffin - updated : 6/2/2016
Matthew B. Gross - updated : 6/20/2013
Cassandra L. Kniffin - updated : 7/8/2009

Creation Date:
Paul J. Converse : 5/17/2000

Edit History:
alopez : 03/31/2022
carol : 10/03/2016
mgross : 06/06/2016
carol : 6/2/2016
ckniffin : 6/2/2016
carol : 5/25/2016
carol : 9/16/2013
mgross : 6/20/2013
carol : 4/4/2011
carol : 7/9/2009
ckniffin : 7/8/2009
carol : 8/4/2000
carol : 5/17/2000