* 617351

IMMUNOGLOBULIN SUPERFAMILY, MEMBER 10; IGSF10


HGNC Approved Gene Symbol: IGSF10

Cytogenetic location: 3q25.1     Genomic coordinates (GRCh38): 3:151,432,432-151,619,925 (from NCBI)


TEXT

Description

IGSF10 belongs to the immunoglobulin (Ig) superfamily and appears to play a role in early migration of GNRH (GNRH1; 152760)-expressing neurons (Howard et al., 2016)


Cloning and Expression

By in silico analysis, Howard et al. (2016) determined that the 2,623-amino acid IGSF10 protein contains an N-terminal signal peptide, followed by 7 leucine-rich repeats, a structurally disordered region, 2 Ig-like beta sandwich domains, another structurally disordered region, and 10 C-terminal Ig-like domains. In situ hybridization detected IGSF10 mRNA in mouse and human nasal mesenchyme near GNRH-expressing cells, but not in olfactory epithelium.


Mapping

Gross (2017) mapped the IGSF10 gene to chromosome 3q25.1 based on an alignment of the IGSF10 sequence (GenBank BC156531) with the genomic sequence (GRCh38).


Gene Function

Howard et al. (2016) observed reduced migration of immature mouse Gnrh neurons across mouse fibroblasts following knockdown of Igsf10. Knockdown of Igsf10 in zebrafish perturbed migration and extension of Gnrh neurons. Howard et al. (2016) proposed that IGSF10 is a component of a complex system of migratory cues guiding GNRH neurons from their origin in the nasal placode toward the hypothalamus during embryogenesis.


Molecular Genetics

Associations Pending Confirmation

By exome sequencing in 18 Finnish probands with delayed puberty in whom a diagnosis of hypogonadotropic hypogonadism had been excluded (see 619613), Howard et al. (2016) identified 2 rare heterozygous missense mutations in the IGSF10 gene in 6 families, including an E161K (c.481G-A, NM_17882244) variant in affected members of 4 families, and R156L (c.467G-T, NM_17882244) in affected members of 2 families. Both mutations were found in the ExAC database (minor allele frequencies, 0.7% and 0.5% in Europeans, and 1.0% and 0.4% in all exomes, respectively). Functional analysis in mammalian cells showed that, unlike wildtype IGSF10, the mutant proteins were not secreted, apparently due to intracellular retention. Targeted exome sequencing in an adult cohort of 334 patients with HH revealed that 34 (10.2%) of the patients were heterozygous for rare IGSF10 variants predicted to be damaging, including 3 truncating variants and 13 missense variants. The authors noted that the 3 truncating variants were enriched in the HH cohort compared to the ExAC database. Howard et al. (2016) concluded that their findings strongly supported a causative role for IGSF10 mutations in delayed puberty, through dysregulation of GnRH neuronal migration during embryonic development.


REFERENCES

  1. Gross, M. B. Personal Communication. Baltimore, Md. 2/16/2017.

  2. Howard, S. R., Guasti, L., Ruiz-Babot, G., Mancini, A., David, A., Storr, H. L., Metherell, L. A., Sternberg, M. J. E., Cabrera, C. P., Warren, H. R., Barnes, M. R., Quinton, R., de Roux, N., Young, J., Guiochon-Mantel, A., Wehkalampi, K., Andre, V., Gothilf, Y., Cariboni, A., Dunkel, L. IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty. EMBO Molec. Med. 8: 626-642, 2016. [PubMed: 27137492, images, related citations] [Full Text]


Marla J. F. O'Neill - updated : 11/10/2021
Marla J. F. O'Neill - updated : 02/27/2017
Matthew B. Gross - updated : 02/16/2017
Creation Date:
Paul J. Converse : 02/16/2017
carol : 11/10/2021
carol : 10/18/2019
carol : 02/27/2017
mgross : 02/16/2017

* 617351

IMMUNOGLOBULIN SUPERFAMILY, MEMBER 10; IGSF10


HGNC Approved Gene Symbol: IGSF10

Cytogenetic location: 3q25.1     Genomic coordinates (GRCh38): 3:151,432,432-151,619,925 (from NCBI)


TEXT

Description

IGSF10 belongs to the immunoglobulin (Ig) superfamily and appears to play a role in early migration of GNRH (GNRH1; 152760)-expressing neurons (Howard et al., 2016)


Cloning and Expression

By in silico analysis, Howard et al. (2016) determined that the 2,623-amino acid IGSF10 protein contains an N-terminal signal peptide, followed by 7 leucine-rich repeats, a structurally disordered region, 2 Ig-like beta sandwich domains, another structurally disordered region, and 10 C-terminal Ig-like domains. In situ hybridization detected IGSF10 mRNA in mouse and human nasal mesenchyme near GNRH-expressing cells, but not in olfactory epithelium.


Mapping

Gross (2017) mapped the IGSF10 gene to chromosome 3q25.1 based on an alignment of the IGSF10 sequence (GenBank BC156531) with the genomic sequence (GRCh38).


Gene Function

Howard et al. (2016) observed reduced migration of immature mouse Gnrh neurons across mouse fibroblasts following knockdown of Igsf10. Knockdown of Igsf10 in zebrafish perturbed migration and extension of Gnrh neurons. Howard et al. (2016) proposed that IGSF10 is a component of a complex system of migratory cues guiding GNRH neurons from their origin in the nasal placode toward the hypothalamus during embryogenesis.


Molecular Genetics

Associations Pending Confirmation

By exome sequencing in 18 Finnish probands with delayed puberty in whom a diagnosis of hypogonadotropic hypogonadism had been excluded (see 619613), Howard et al. (2016) identified 2 rare heterozygous missense mutations in the IGSF10 gene in 6 families, including an E161K (c.481G-A, NM_17882244) variant in affected members of 4 families, and R156L (c.467G-T, NM_17882244) in affected members of 2 families. Both mutations were found in the ExAC database (minor allele frequencies, 0.7% and 0.5% in Europeans, and 1.0% and 0.4% in all exomes, respectively). Functional analysis in mammalian cells showed that, unlike wildtype IGSF10, the mutant proteins were not secreted, apparently due to intracellular retention. Targeted exome sequencing in an adult cohort of 334 patients with HH revealed that 34 (10.2%) of the patients were heterozygous for rare IGSF10 variants predicted to be damaging, including 3 truncating variants and 13 missense variants. The authors noted that the 3 truncating variants were enriched in the HH cohort compared to the ExAC database. Howard et al. (2016) concluded that their findings strongly supported a causative role for IGSF10 mutations in delayed puberty, through dysregulation of GnRH neuronal migration during embryonic development.


REFERENCES

  1. Gross, M. B. Personal Communication. Baltimore, Md. 2/16/2017.

  2. Howard, S. R., Guasti, L., Ruiz-Babot, G., Mancini, A., David, A., Storr, H. L., Metherell, L. A., Sternberg, M. J. E., Cabrera, C. P., Warren, H. R., Barnes, M. R., Quinton, R., de Roux, N., Young, J., Guiochon-Mantel, A., Wehkalampi, K., Andre, V., Gothilf, Y., Cariboni, A., Dunkel, L. IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty. EMBO Molec. Med. 8: 626-642, 2016. [PubMed: 27137492] [Full Text: https://doi.org/10.15252/emmm.201606250]


Contributors:
Marla J. F. O'Neill - updated : 11/10/2021
Marla J. F. O'Neill - updated : 02/27/2017
Matthew B. Gross - updated : 02/16/2017

Creation Date:
Paul J. Converse : 02/16/2017

Edit History:
carol : 11/10/2021
carol : 10/18/2019
carol : 02/27/2017
mgross : 02/16/2017