Alternative titles; symbols
HGNC Approved Gene Symbol: HYCC1
SNOMEDCT: 702379005;
Cytogenetic location: 7p15.3 Genomic coordinates (GRCh38) : 7:22,895,843-23,014,130 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p15.3 | Leukodystrophy, hypomyelinating, 5 | 610532 | Autosomal recessive | 3 |
Kawasoe et al. (2000) identified FAM126A, which they called DRCTNNB1A, as a 521-amino acid protein whose expression was downregulated by beta-catenin (116806). Zara et al. (2006), who referred to the protein as hyccin, noted the presence of putative orthologs in different species. RNA blot analysis showed that DRCTNNB1A is expressed in several adult tissues including heart, kidney, and placenta, and is ubiquitously expressed in brain. Using RT-PCR, Zara et al. (2006) showed that DRCTNNB1A is expressed in the lens.
Kawasoe et al. (2000) mapped the FAM126A gene to chromosome 7p15.3 by FISH.
The process of myelination occurs as an interplay between glial cells and neurons. The findings of Zara et al. (2006) indicated that hyccin is essential for proper myelination in both the central and peripheral nervous system.
By proteomic analysis in HeLa cells, Baskin et al. (2016) confirmed that TTC7B (620060), ERF3A (611798), and EFR3B (616797) were components of the PI4KIII-alpha (PI4KA; 600286) complex. They identified FAM126A or FAM126B (HYCC2) as additional components of the PI4KIII-alpha complex. TTC7B played a central role in bridging PI4KIII-alpha to EFR3B. Moreover, FAM126A bound directly to TTC7B through its N-terminal portion to form a heterodimer, and FAM126A-TTC7B bound to PI4KIII-alpha simultaneously to form a ternary complex. Interaction of PI4KIII-alpha with TTC7B and FAM126A appeared to stabilize the PI4KIII-alpha fold and stimulate catalytic activity. Moreover, FAM126A loss or reduction in mouse or human destabilized and degraded PI4KIII-alpha complex components and affected PI4KIII-alpha complex assembly and PI4KIII-alpha-mediated PtdIns4P synthesis at the plasma membrane.
Baskin et al. (2016) determined the crystal structure of TTC7B in complex with the N-terminal portion of FAM126A (FAM126A-N, residues 1 to 289) at 2.9-angstrom resolution. Both proteins were almost entirely alpha helical. TTC7B alpha helices were arranged into a superhelix, with the C-terminal peptide inserted into the center of the superhelix. In contrast, FAM126A-N was globular, except for a long hairpin (residues 121 to 165) that extended out and wrapped around TTC7B. The 2 proteins interacted to form a large interface conserved in metazoans, as well as a conserved binding surface for PI4KIII-alpha. The structural data supported the stabilizing function proposed for TTC7B and FAM126A in the PI4KIII-alpha complex.
By systematic screening of all 31 transcripts in a critical linkage region on 7p21.3-p15.3 identified in families with hypomyelinating leukodystrophy-5 (HLD5; 610532), which is associated with congenital cataract, Zara et al. (2006) detected 3 mutations in the DRCTNNB1A gene in 5 families. Two affected a splice site (610531.0001, 610531.0002) and the third was a missense mutation (610531.0003). Zara et al. (2006) concluded that their findings indicated the presence of a molecular link between cerebral and peripheral myelination disorders and congenital cataract.
Ugur and Tolun (2008) identified a homozygous intragenic deletion in the FAM126A gene (610531.0004) in affected members of a consanguineous Turkish family with hypomyelinating leukodystrophy and congenital cataracts. One patient developed cataracts at age 9 years.
In 6 individuals in 3 families, Zara et al. (2006) demonstrated that hypomyelinating leukodystrophy-5 (HLD5; 610532) was associated with a splice site mutation in the FAM126A gene: IVS2+1G-A. One patient had lost the ability to walk with support at the age of 8 years and showed pyramidal and cerebellar signs as well as signs of peripheral neuropathy. An affected male in another family lost the ability to walk with support at the age of 9 years.
In 3 sibs with hypomyelination and congenital cataract (HLD5; 610532), Zara et al. (2006) observed a splice site mutation of the FAM126A gene: IVS5+1G-T.
Biancheri et al. (2011) identified homozygosity for the IVS5+1G-T mutation in 4 unrelated patients with HLD5 from the Mediterranean region. Haplotype analysis of 3 of these patients and the patient reported by Zara et al. (2006) suggested a founder effect.
In a patient with hypomyelination and congenital cataract (HLD5; 610532), Zara et al. (2006) observed a 158T-C transition in the FAM126A gene, predicted to cause a leu53-to-pro (L53P) amino acid change in the hyccin protein. A residual amount of hyccin protein was found in this patient, who manifested a relatively mild phenotype; this finding suggested a correlation between reduced protein level and phenotypic severity.
In 3 patients from a consanguineous Turkish family with hypomyelinating leukodystrophy and congenital cataracts (HLD5; 610532), Ugur and Tolun (2008) identified a homozygous intragenic 4,084-bp deletion (531-439_743+348del) in the FAM126A gene, resulting in skipping of exon 8 and 9, frameshift at the beginning of exon 10, and premature termination at codon 214. The region of the deletion was flanked by an 82- and 83-bp direct repeat, suggesting that it resulted from unequal crossover. Clinical details of the 10-year-old male proband included congenital bilateral cataract, psychomotor regression beginning around 1 year of age, moderate mental retardation, and white matter changes in supratentorial structures and paraventricular regions. He also had a sensorimotor peripheral demyelinating neuropathy and never achieved walking. Two other affected individuals died at ages 2 and 12 years, respectively. One of the patients developed cataracts at age 9 years.
Baskin, J. M., Wu, X., Christiano, R., Oh, M. S., Schauder, C. M., Gazzerro, E., Messa, M., Baldassari, S., Assereto, S., Biancheri, R., Zara, F., Minetti, C., Raimondi, A., Simons, M., Walther, T. C., Reinisch, K. M., De Camilli, P. The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane. Nat. Cell Biol. 18: 132-138, 2016. [PubMed: 26571211] [Full Text: https://doi.org/10.1038/ncb3271]
Biancheri, R., Zara, F., Rossi, A., Mathot, M., Nassogne, M. C., Yalcinkaya, C., Erturk, O., Tuysuz, B., Di Rocco, M., Gazzerro, E., Bugiani, M., van Spaendonk, R., Sistermans, E. A., Minetti, C., van der Knaap, M. S., Wolf, N. I. Hypomyelination and congenital cataract: broadening the clinical phenotype. Arch. Neurol. 68: 1191-1194, 2011. [PubMed: 21911699] [Full Text: https://doi.org/10.1001/archneurol.2011.201]
Kawasoe, T., Furukawa, Y., Daigo, Y., Nishiwaki, T., Ishiguro, H., Fujita, M., Satoh, S., Miwa, N., Nagasawa, Y., Miyoshi, Y., Ogawa, M., Nakamura, Y. Isolation and characterization of a novel human gene, DRCTNNB1A, the expression of which is down-regulated by beta-catenin. Cancer Res. 60: 3354-3358, 2000. [PubMed: 10910037]
Ugur, S. A., Tolun, A. A deletion in DRCTNNB1A associated with hypomyelination and juvenile onset cataract. Europ. J. Hum. Genet. 16: 261-264, 2008. [PubMed: 17928815] [Full Text: https://doi.org/10.1038/sj.ejhg.5201935]
Zara, F., Biancheri, R., Bruno, C., Bordo, L., Assereto, S., Gazzerro, E., Sotgia, F., Wang, X. B., Gianotti, S., Stringara, S., Pedemonte, M., Uziel, G., Rossi, A., Schenone, A., Tortori-Donati, P., van der Knaap, M. S., Lisanti, M. P., Minetti, C. Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract. Nature Genet. 38: 1111-1113, 2006. [PubMed: 16951682] [Full Text: https://doi.org/10.1038/ng1870]