Alternative titles; symbols
HGNC Approved Gene Symbol: GFER
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:1,984,193-1,987,749 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Myopathy, mitochondrial progressive, with congenital cataract and developmental delay | 613076 | Autosomal recessive | 3 |
The hepatotrophic factor designated augmenter of liver regeneration (ALR) is thought to be one of the factors responsible for the extraordinary regenerative capacity of mammalian liver (Francavilla et al., 1994). It has also been called hepatic regenerative stimulation substance (HSS). Hagiya et al. (1994) cloned and sequenced a rat gene they designated Alr. The gene encodes a 125-amino acid polypeptide with a calculated molecular mass of 15,081 Da, consistent with its electrophoretically determined molecular weight under reducing conditions. The deduced primary sequence is 50% homologous to the polypeptide encoded by the scERV1 oxidative phosphorylation and vegetative growth gene in S. cerevisiae. Hagiya et al. (1994) determined that the protein functions as a homodimer and found expression of the 1.2-kb gene transcript to be highest in rat testis and liver. In an erratum, Hagiya et al. (1994) corrected their reported cDNA sequence. They found that whereas the single G insertion at cDNA position 266 did not alter the gene coding region, it did generate 2 additional in-frame initiation sites that are 5-prime of the initiation site they had originally reported. They raised the possibility of other ALR 'long form' variants.
Lisowsky et al. (1995) identified a human gene on chromosome 16 in the interval containing the locus for polycystic kidney disease (PKD1; 173900) by analysis of a genomic cosmid clone and cDNAs. The gene is actively transcribed in tissues from kidney and brain. The putative gene product is 42% identical to the scERV1 protein of yeast. The yeast scERV1 gene had been found to be essential for oxidative phosphorylation, the maintenance of mitochondrial genomes, and the cell division cycle.
Giorda et al. (1996) used a rat Alr gene probe from the Hagiya et al. (1994) sequence to clone and characterize the mouse Alr gene and its human homolog. The human ALR gene contains 205 amino acids, compared to 198 for the mouse and rat protein sequences they reported. The human, rat, and mouse proteins are highly conserved. Giorda et al. (1996) found that rat, mouse, and human ALR genes are preferentially expressed in the testis and liver.
Lisowsky et al. (1995) determined that the ALR gene contains at least 1 intron.
Giorda et al. (1996) showed that the protein-coding portion of the mouse ALR gene contains 3 exons, the first containing the 5-prime untranslated sequence and the initial 18 bp after the ATG translation initiation codon. The second exon contains 198 bp and the third exon contains the remaining portion of the protein coding sequence.
Di Fonzo et al. (2009) stated that the GFER gene codes for 2 distinct isoforms that are probably synthesized from the same mRNA with the use of different initiation codons. The long isoform (205 amino acids, 23 kD) is located mainly in the mitochondrial intermembrane space and exists under nonreducing and nondenaturing conditions as a homodimer and a heterodimer. The shorter isoform (125 amino acids, 15 kD), which lacks 80 amino acids at its N terminus compared to the longer isoform, is present predominantly in the nucleus (Li et al., 2002).
Giorda et al. (1996) mapped the GFER gene to chromosome 16 using a panel of monochromosomal hybrid cell lines for analysis by PCR. They mapped the mouse homolog to chromosome 17, in a region syntenic with human chromosome 16, by hybridization to an interspecies backcross panel.
Gross (2021) mapped the GFER gene to chromosome 16p13.3 based on an alignment of the GFER sequence (GenBank AF183892) with the genomic sequence (GRCh38).
Lisowsky et al. (1995) transformed yeast mutants defective in scERV1 with a yeast expression vector containing a chimeric reading frame which joins the first 21 amino acids of the yeast protein and the terminal 100 amino acids of the human protein. The chimeric human gene product complemented the yeast mutants and restored near-normal viability. Thus Lisowsky et al. (1995) concluded that the human gene is not only the structural but also the functional homolog of the yeast scERV1 gene.
Di Fonzo et al. (2009) showed that GFER plays an important role in the disulfide relay system (DRS) in human mitochondria.
Daithankar et al. (2010) determined the crystal structure of the short isoform of human ALR by molecular replacement using the rat structure. The human structure was an asymmetric unit consisting of 3 subunits: a disulfide-linked homodimer and half of an adjacent dimer. Arg194, which is mutated to his194 (R194H; 600924.0001) in progressive mitochondrial myopathy and combined respiratory chain deficiency (MPMCD; 613076), was involved in formation of 3 hydrogen bonds and was located at the subunit interface of ALR. Further analysis showed that the R194H mutation had a large effect on protein stability and flavin binding, but that it did not impact enzyme activity and other biophysical features of ALR.
In a consanguineous Moroccan family segregating an autosomal recessive mitochondrial myopathy with cataract and combined respiratory chain deficiency (613076), Di Fonzo et al. (2009) identified homozygosity for a missense mutation in the GFER gene (R194H; 600924.0001).
By next-generation sequencing of a nuclear gene panel for mitochondrial disease, Calderwood et al. (2016) identified a patient with mitochondrial myopathy, cataracts, and developmental delay who was compound heterozygous for mutations in the GFER gene: the previously identified R194H mutation and a novel nonsense mutation (Q125X; 600294.0002).
In a proband and his sister with MPMCD, Thevenon et al. (2016) and Nambot et al. (2017) identified compound heterozygous frameshift mutations in the GFER gene (600924.0003; 600924.0004). In 2 other sibs with MPMCD, Nambot et al. (2017) identified compound heterozygous mutations in the GFER gene: R194H and a frameshift mutation (600924.0005). The mutations segregated with the disorder in both families. None of the mutations were found in the ExAC database.
In 3 children born to consanguineous Moroccan parents with a progressive mitochondrial myopathy and combined respiratory chain deficiency (MPMCD; 613076), Di Fonzo et al. (2009) identified a homozygous G-to-A transition at nucleotide 581 in exon 3 of the GFER gene, resulting in an arg-to-his substitution at codon 194 (R194H). This mutation was not identified in 380 samples from unrelated European individuals and 183 samples from unrelated Arab individuals, including 156 Moroccans. Confocal microscopy and immunoblot analysis showed that R194H mutant GFER is less stable than wildtype protein within the mitochondria.
By next-generation sequencing of a nuclear gene panel for mitochondrial disease, Calderwood et al. (2016) identified a patient with MPMCD who was compound heterozygous for mutations in the GFER gene: R194H and a c.373C-T transition, resulting in a gln125-to-ter substitution (Q125X; 600294.0002). This patient also had adrenal insufficiency and had previously been reported by North et al. (1996).
In 2 sibs (patients 3 and 4) with MPMCD, Nambot et al. (2017) identified compound heterozygous mutations in the GFER gene: R194H and a 1-bp deletion in exon 1 (c.217delG; 600924.0005), resulting in a frameshift and a premature stop codon (600924.0005). Each parent was heterozygous for one of the mutations. Neither variant was present in the ExAC database.
Variant Function
Ceh-Pavia et al. (2014) characterized recombinant yeast Erv1 containing an R182H mutation, which corresponds to the R194H mutation in the human ortholog. The mutation did not affect the FAD content of Erv1, but it disturbed the secondary, tertiary, and quaternary structures of Erv1, with the mutant protein forming a dimer instead of a tetramer like wildtype. The Erv1 R182H mutant had both decreased thermal stability and weaker FAD-binding compared with wildtype. The mutation not only caused a defect in Erv1 shuttling of electrons to molecular oxygen, but also in the ability of Erv1 to reduce cytochrome c. The gradual inactivation of Erv1 resulted from loss of cofactor during the catalytic reaction, and this functional defect could be rescued with the addition of extra FAD or excessive Erv1 in vitro. Likewise, the growth defect of the Erv1 R182H mutant yeast strain could be rescued by increasing the concentration of the mutant protein through overexpression in vivo.
By structural and other analyses of human ALR, Daithankar et al. (2010) found that the R194H mutation had a large effect on protein stability and flavin binding, but that it did not impact enzyme activity and other biophysical features of ALR.
For discussion of the c.373C-T transition in the GFER gene, resulting in a gln125-to-ter (Q125X) substitution, that was found in compound heterozygous state in a patient with mitochondrial myopathy, cataracts, and developmental delay (MPMCD; 613076) by Calderwood et al. (2016), see 600924.0001.
By whole-exome sequencing in a brother and sister with mitochondrial myopathy, congenital cataract, and developmental delay (MPMCD; 613076), Thevenon et al. (2016) and Nambot et al. (2017) identified compound heterozygous mutations in the GFER gene: a 1-bp deletion (c.219delC, NM_005262.2) in exon 1, resulting in a frameshift and a premature termination codon (Cys74AlafsTer76), and a 2-bp deletion (c.259-25_259-25delCA; 600924.0004) in the start of exon 2, resulting in a frameshift and a premature termination codon. The mutations segregated with the disorder in the family. Neither variant was present in the ExAC database.
For discussion of the 2-bp deletion (c.259-25_259-24, NM_005262.2) in the start of exon 2 in the GFER gene, resulting in a frameshift and a premature truncation codon, that was found in compound heterozygous state in sibs with mitochondrial myopathy, cataracts, and developmental delay (MPMCD; 613076) by Nambot et al. (2017), see 600924.0003.
For discussion of the 1-bp deletion (c.217delG, NM_005262.2) in exon 1 of the GFER gene, resulting in a frameshift and a premature termination codon (Ala73ProfsTer77), that was found in compound heterozygous state in sibs with mitochondrial myopathy, cataracts, and developmental delay (MPMCD; 613076) by Nambot et al. (2017), see 600924.0001.
Calderwood, L., Holm, I. A., Teot, L. A., Anselm, I. Adrenal insufficiency in mitochondrial disease: a rare case of GFER-related mitochondrial encephalomyopathy and review of the literature. J. Child Neurol. 31: 190-194, 2016. [PubMed: 26018198] [Full Text: https://doi.org/10.1177/0883073815587327]
Ceh-Pavia, E., Ang, S. K., Spiller, M. P., Lu, H. The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction. Biochem. J. 464: 449-459, 2014. [PubMed: 25269795] [Full Text: https://doi.org/10.1042/BJ20140679]
Daithankar, V. N., Schaefer, S. A., Dong, M., Bahnson, B. J., Thorpe, C. Structure of the human sulfhydryl oxidase augmenter of liver regeneration and characterization of a human mutation causing an autosomal recessive myopathy. Biochemistry 49: 6737-6745, 2010. [PubMed: 20593814] [Full Text: https://doi.org/10.1021/bi100912m]
Di Fonzo, A., Ronchi, D., Lodi, T., Fassone, E., Tigano, M., Lamperti, C., Corti, S., Bordoni, A., Fortunato, F., Nizzardo, M., Napoli, L., Donadoni, C., Salani, S., Saladino, F., Moggio, M., Bresolin, N., Ferrero, I., Comi, G. P. The mitochondrial disulfide relay system protein GFER is mutated in autosomal-recessive myopathy with cataract and combined respiratory-chain deficiency. Am. J. Hum. Genet. 84: 594-604, 2009. [PubMed: 19409522] [Full Text: https://doi.org/10.1016/j.ajhg.2009.04.004]
Francavilla, A., Hagiya, M., Porter, K. A., Polimeno, L., Ihara, I., Starzl, T. E. Augmenter of liver regeneration: its place in the universe of hepatic growth factors. Hepatology 20: 747-757, 1994. [PubMed: 8076931]
Giorda, R., Hagiya, M., Seki, T., Shimonishi, M., Sakai, H., Michaelson, J., Francavilla, A., Starzl, T. E., Trucco, M. Analysis of the structure and expression of the augmenter of liver regeneration (ALR) gene. Molec. Med. 2: 97-108, 1996. [PubMed: 8900538]
Gross, M. B. Personal Communication. Baltimore, Md. 3/12/2021.
Hagiya, M., Francavilla, A., Polimeno, L., Ihara, I., Sakai, H., Seki, T., Shimonishi, M., Porter, K. A., Starzl, T. E. Cloning and sequence analysis of the rat augmenter of liver regeneration (ALR) gene: expression of biologically active recombinant ALR and demonstration of tissue distribution. Proc. Nat. Acad. Sci. 91: 8142-8146, 1994. Note: Erratum Proc. Nat. Acad. Sci. 92, p. 3076 only, 1995. [PubMed: 8058770] [Full Text: https://doi.org/10.1073/pnas.91.17.8142]
Li, Y., Wei, K., Lu, C., Li, Y., Li, M., Xing, G., Wei, H., Wang, Q., Chen, J., Wu, C., Chen, H., Yang, S., He, F. Identification of hepatopoietin dimerization, its interacting regions and alternative splicing of its transcription. Europ. J. Biochem. 269: 3888-3893, 2002. [PubMed: 12180965] [Full Text: https://doi.org/10.1046/j.1432-1033.2002.03054.x]
Lisowsky, T., Weinstat-Saslow, D. L., Barton, N., Reeders, S. T., Schneider, M. C. A new human gene located in the PKD1 region of chromosome 16 is a functional homologue to ERV1 of yeast. Genomics 29: 690-697, 1995. [PubMed: 8575761] [Full Text: https://doi.org/10.1006/geno.1995.9950]
Nambot, S., Gavrilov, D., Thevenon, J., Bruel, A. L., Bainbridge, M., Rio, M., Goizet, C., Rotig, A., Jaeken, J., Niu, N., Xia, F., Vital, A., Houcinat, N., Mochel, F., Kuentz, P., Lehalle, D., Duffourd, Y., Riviere, J. B., Thauvin-Robinet, C., Beaudet, A. L., Faivre, L. Further delineation of a rare recessive encephalomyopathy linked to mutations in GFER thanks to data sharing of whole exome sequencing data. Clin. Genet. 92: 188-198, 2017. [PubMed: 28155230] [Full Text: https://doi.org/10.1111/cge.12985]
North, K., Korson, M. S., Krawiecki, N., Shoffner, J. M., Holm, I. A. Oxidative phosphorylation defect associated with primary adrenal insufficiency. J. Pediat. 128: 688-692, 1996. [PubMed: 8627443] [Full Text: https://doi.org/10.1016/s0022-3476(96)80136-3]
Thevenon, J., Duffourd, Y., Masurel-Paulet, A., Lefebvre, M., Feillet, F., El Chehadeh-Djebbar, S., St-Onge, J., Steinmetz, A., Huet, F., Chouchane, M., Darmency-Stamboul, V., Callier, P., Thauvin-Robinet, C., Faivre, L., Riviere, J. F. Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test. Clin. Genet. 89: 700-707, 2016. [PubMed: 26757139] [Full Text: https://doi.org/10.1111/cge.12732]