Alternative titles; symbols
HGNC Approved Gene Symbol: AFG2A
SNOMEDCT: 1254651003;
Cytogenetic location: 4q28.1 Genomic coordinates (GRCh38): 4:122,923,078-123,319,433 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q28.1 | Neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities | 616577 | Autosomal recessive | 3 |
Liu et al. (2000) cloned mouse Spata5, which they called Spaf. The deduced 892-amino acid protein contains a putative mitochondrial localization signal and 2 ATPase modules typical of AAA family proteins (see 601681). Northern blot analysis of mouse tissues detected high expression of a 3-kb Spaf transcript in testis, with much weaker expression in spleen and little to no expression in other tissues examined. Spaf was also highly expressed as 3- and 1.7-kb transcripts in mouse 03RAT cells, which were derived from a poorly differentiated squamous cell carcinoma. Immunohistochemical analysis detected Spaf in prepubertal and adult mouse testis, where it was expressed in spermatogonia and early spermatocytes up to the zygotene stage. Spaf was not detected in somatic cells of testis. Spaf distributed diffusely throughout the cytoplasm of germ cells and also localized to mitochondria. Western blot analysis detected endogenous and in vitro-translated Spaf at an apparent molecular mass of 97 kD.
Hartz (2011) mapped the SPATA5 gene to chromosome 4q28.1 based on an alignment of the SPATA5 sequence (GenBank AF361489) with the genomic sequence (GRCh37).
In 14 children from 10 families with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577), Tanaka et al. (2015) identified homozygous or compound heterozygous mutations in the SPATA5 gene (see, e.g., 613940.0001-613940.0005). The mutations were found by whole-exome sequencing and segregated with the disorder in the families. Functional studies of the variants were not performed.
In 3 children from 2 Japanese families with NEDHSB, Kurata et al. (2016) identified compound heterozygous mutations in the SPATA5 gene (see, e.g., 613940.0006-613940.0007). The mutations were found by whole-exome and confirmed by Sanger sequencing. No functional studies were performed.
In 2 sisters (individuals 1 and 2) with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577), Tanaka et al. (2015) identified compound heterozygous mutations in the SPATA5 gene: a c.2531C-T transition (c.2531C-T, NM_145207.2), resulting in an ala844-to-val (A844V) substitution at a highly conserved residue, and a 5-bp deletion (c.1574_1578delATGCT; 613940.0002), resulting in a frameshift and premature termination (Asn525ThrfsTer20). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variants were not performed.
For discussion of the 5-bp deletion (c.1574_1578delATGCT, NM_145207.2) in the SPATA5 gene, resulting in a frameshift and premature termination (Asn525ThrfsTer20), that was identified in 2 sisters with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577) by Tanaka et al. (2015), see 613940.0001.
In a 4-year-old girl (individual 4) with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577), Tanaka et al. (2015) identified compound heterozygous mutations in the SPATA5 gene: a c.1343C-T transition (c.1343C-T, NM_145207.2), resulting in a ser448-to-leu (S448L) substitution at a highly conserved residue in the first AAA domain, and a c.556C-T transition, resulting in an arg186-to-ter (R186X; 613940.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The c.1343C-T mutation was found at a very low frequency (less than 1 in 10,000) in the ExAC database, but not in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases; c.556C-T was not found in any of the control databases. Functional studies of the variants were not performed.
For discussion of the c.556C-T transition (c.556C-T, NM_145207.2) in the SPATA5 gene, resulting in an arg186-to-ter (R186X) substitution, that was found in compound heterozygous state in 2 unrelated patients with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577) by Tanaka et al. (2015), see 613940.0003 and 613940.0005. The mutation was part of a shared haplotype in both patients, who were of European descent.
In a 2-year-old girl (individual 5) with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577), Tanaka et al. (2015) identified compound heterozygous mutations in the SPATA5 gene: a c.298G-A transition (c.298G-A, NM_145207.2), resulting in an ala100-to-thr (A100T) substitution at a highly conserved residue in the CDC48 N-terminal domain, and R186X (613940.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. Functional studies of the variants were not performed.
In 2 sibs with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577), Kurata et al. (2016) identified compound heterozygous mutations in the SPATA5 gene: a 3-bp deletion (c.989_991del, NM_145207.2), resulting in an in-frame deletion of thr330 (Thr330del), inherited from the mother, and a 4-bp deletion (c.2130_2133del; 613940.0007), resulting in a frameshift and premature termination (Glu711ProfsTer21), inherited from the father. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. No functional studies were performed.
For discussion of the 4-bp deletion (c.2130_2133del, NM_145207.2) in the SPATA5 gene, resulting in a frameshift and premature termination (Glu711ProfsTer21), that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with hearing loss, seizures, and brain abnormalities (NEDHSB; 616577) by Kurata et al. (2016), see 613940.0006.
Hartz, P. A. Personal Communication. Baltimore, Md. 4/19/2011.
Kurata, H., Terashima, H., Nakashima, M., Matsumura, W., Ohno, K., Saito, Y., Maegaki, Y., Kubota, M., Nanba, E., Saitsu, H., Matsumoto, N., Kato, M. Characterization of SPATA5-related encephalopathy in early childhood. Clin. Genet. 90: 437-444, 2016. [PubMed: 27246907] [Full Text: https://doi.org/10.1111/cge.12813]
Liu, Y., Black, J., Kisiel, N., Kulesz-Martin, M. F. SPAF, a new AAA-protein specific to early spermatogenesis and malignant conversion. Oncogene 19: 1579-1588, 2000. [PubMed: 10734318] [Full Text: https://doi.org/10.1038/sj.onc.1203442]
Tanaka, A. J., Cho, M. T., Millan, F., Juusola, J., Retterer, K., Joshi, C., Niyazov, D., Garnica, A., Gratz, E., Deardorff, M., Wilkins, A., Ortiz-Gonzalez, X., and 11 others. Mutations in SPATA5 are associated with microcephaly, intellectual disability, seizures, and hearing loss. Am. J. Hum. Genet. 97: 457-464, 2015. [PubMed: 26299366] [Full Text: https://doi.org/10.1016/j.ajhg.2015.07.014]