Alternative titles; symbols
ORPHA: 369962; DO: 0111814;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Methylmalonic aciduria and homocysteinemia, cblX type | 309541 | X-linked recessive | 3 | HCFC1 | 300019 |
A number sign (#) is used with this entry because methylmalonic aciduria and homocystinuria of the cblX type (MAHCX) is caused by mutation in the HCFC1 gene (300019) on chromosome Xq28. Some patients have X-linked intellectual developmental disorder (XLID3) without the cobalamin disorder.
Methylmalonic aciduria and homocystinemia of the cblX type (MAHCX) is an X-linked recessive metabolic disorder characterized by severely delayed psychomotor development apparent in infancy. It is associated with failure to thrive, impaired intellectual development, and intractable epilepsy. Additional features may include microcephaly and choreoathetosis (summary by Yu et al., 2013).
Gedeon et al. (1991) reported a large family with nonsyndromic X-linked intellectual developmental disorder. Huang et al. (2012) reported follow-up of this family. Affected males were generally nondysmorphic, although some had mild features, such as small chin, high-arched palate, or tapered fingers. Many had below average height and brachycephaly. Intellectual disability ranged from mild to moderate; some males lived semi-independently with supervised employment, whereas others needed full-time supervision. Many showed behavioral problems, including aggression, whereas others were reclusive and had some autistic traits. Obligate carrier females were normal and had high skewing of X inactivation. Huang et al. (2012) reported another family with XLID3. The proband had mild intellectual disability and attended a school for special needs. At age 17 years, he had anxiety and a tendency for compulsive behavior. His brother was also affected; he had hyperopia and deficits in fine motor skills. Biochemical studies were not reported in the families studied by Huang et al. (2012).
Yu et al. (2013) reported 14 unrelated males with severely delayed psychomotor development apparent since infancy and associated with mental retardation, failure to thrive, and intractable epilepsy. Some patients had additional neurologic dysfunction, such as choreoathetosis and hypsarrhythmia on EEG. Microcephaly was common. The patients were ascertained through laboratory findings suggestive of a cobalamin disorder. Most patients had combined methylmalonic acidemia and homocysteinemia, although 5 had normal plasma homocysteine. Complementation analysis in most of the patients suggested cblC type (277400), but molecular analysis excluded mutations in the MMACHC gene (609831).
Gedeon et al. (1991) described a family with nonspecific X-linked intellectual developmental disorder showing linkage to DXS52 (St14) located on the terminal band of the X chromosome, Xq28; maximum lod score = 2.89 at theta = 0.0. The locus was designated MRX3. A recombinant was observed with DXS304, which is known to be proximal to DXS52 but distal to IDS (300823), and the fragile site FRAXA (see 309550) (Suthers et al., 1990). Thus, MRX3 is presumably located in the distal half of Xq28. Kerr et al. (1991) reviewed the topic of nonspecific X-linked mental retardation and proposed a classification based on genetic localization.
Nordstrom et al. (1992) reported a family in which 5 markers in the Xq28 band showed positive lod scores for linkage with nonspecific X-linked intellectual developmental disorder, all at theta = 0.0. The highest lod score, 2.52, was with DXS52. The locus was designated MRX25. Nordstrom et al. (1992) quoted Ott (1991) as stating that the maximum lod score of 2.0 is sufficient to indicate linkage in the case of X-linked diseases.
Holinski-Feder et al. (1996) reported a family in which nonspecific X-linked intellectual developmental disorder showed linkage within a 14-cM interval at Xq28, distal to marker DXS52. The maximum lod score was 2.75 with DXS52. They designated the locus MRX28.
In affected members of the family with XLID3 originally reported by Gedeon et al. (1991), Huang et al. (2012) identified a 455A-G transition in the 5-prime untranslated region of the HCFC1 gene (300019.0001) that disrupted a binding site for the transcription factor YY1 (600013). HCFC1 mRNA was 1.6-fold higher in patient lymphoblastoid cells compared to controls. Overexpression of the Hcfc1 gene in cultured murine neuronal stem cells resulted in a significant reduction of cells in the proliferative stage, promotion of cell cycle exit, and increased production of astrocytes. Overexpression of the Hcfc1 gene in embryonic hippocampal neurons caused a reduction in neurite growth, a reduction in the degree of neurite arborization, and increased neuronal death. The findings suggested that HCFC1 is a potent regulator of embryonic neural development. Microarray data of gene expression showed deregulation of multiple genes involved in mitochondrial function or biogenesis in patients with MRX3 compared to controls. Exome sequencing of additional probands from families with X-linked intellectual developmental disorder found a missense mutation in the HCFC1 gene (S225N; 300019.0002) in 1 proband that segregated with the disorder in that family. Two additional variants in the HCFC1 gene were identified in 2 more probands, but each proband also carried a mutation in another gene (ZMYM3, 300061 and MED13, 300118, respectively), so the contribution of the HCFC1 change to the phenotype could not adequately be determined.
In 14 unrelated males with X-linked intellectual developmental disorder and a cobalamin disorder identified through laboratory studies (cblX), Yu et al. (2013) identified 5 different hemizygous missense mutations in the HCFC1 gene (see, e.g., 300019.0003-300019.0005). Nine of the patients carried the same mutation (A115V; 300019.0003). All mutations occurred at highly conserved residues in 2 of the 5 N-terminal kelch domains. The mutation in the first patient was found by exome sequencing, and the subsequent mutations were found by HCFC1 screening of 17 males with a similar disorder and laboratory findings. Fibroblasts from 2 patients showed decreased mRNA and protein levels of MMACHC, whereas mRNA and protein levels of HCFC1 were normal. Knockdown of HCFC1 in HEK293 cells downregulated MMACHC. These finding suggested that mutations in HCFC1 inhibit its function in the transcriptional activation of MMACHC, and showed that perturbation of transcription can cause an inborn error of metabolism.
Gedeon, A., Kerr, B., Mulley, J., Turner, G. Localisation of the MRX3 gene for non-specific X linked mental retardation. J. Med. Genet. 28: 372-377, 1991. [PubMed: 1870093] [Full Text: https://doi.org/10.1136/jmg.28.6.372]
Holinski-Feder, E., Golla, A., Rost, I., Seidel, H., Rittinger, O., Meindl, A. Regional localization of two MRX genes to Xq28 (MRX28) and to Xp11.4-Xp22.12 (MRX33). Am. J. Med. Genet. 64: 125-130, 1996. [PubMed: 8826462] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960712)64:1<125::AID-AJMG21>3.0.CO;2-O]
Huang, L., Jolly, L. A., Willis-Owen, S., Gardner, A., Kumar, R., Douglas, E., Shoubridge, C., Wieczorek, D., Tzschach, A., Cohen, M., Hackett, A., Field, M., Froyen, G., Hu, H., Haas, S. A., Ropers, H.-H., Kalscheuer, V. M., Corbett, M. A., Gecz, J. A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability. Am. J. Hum. Genet. 91: 694-702, 2012. [PubMed: 23000143] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.011]
Kerr, B., Turner, G., Mulley, J., Gedeon, A., Partington, M. Non-specific X linked mental retardation. J. Med. Genet. 28: 378-382, 1991. [PubMed: 1870094] [Full Text: https://doi.org/10.1136/jmg.28.6.378]
Nordstrom, A.-M., Penttinen, M., von Koskull, H. Linkage to Xq28 in a family with nonspecific X-linked mental retardation. Hum. Genet. 90: 263-266, 1992. [PubMed: 1362558] [Full Text: https://doi.org/10.1007/BF00220075]
Ott, J. Analysis of Human Genetic Linkage. Baltimore: Johns Hopkins Univ. Press (pub.) 1991.
Suthers, G. K., Hyland, V. J., Callan, D. F., Oberle, I., Rocchi, M., Thomas, N. S., Morris, C. P., Schwartz, C. E., Schmidt, M., Ropers, H. H., Baker, E., Oostra, B. A., Dahl, N., Wilson, P. J., Hopwood, J. J., Sutherland, G. R. Physical mapping of new DNA probes near the fragile X mutation (FRAXA) by using a panel of cell lines. Am. J. Hum. Genet. 47: 187-195, 1990. [PubMed: 2378346]
Yu, H.-C., Sloan, J. L., Scharer, G., Brebner, A., Quintana, A. M., Achilly, N. P., Manoli, I., Coughlin, C. R., II, Geiger, E. A., Schneck, U., Watkins, D., Suormala, T., Van Hove, J. L. K., Fowler, B., Baumgartner, M. R., Rosenblatt, D. S., Venditti, C. P., Shaikh, T. H. An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1. Am. J. Hum. Genet. 93: 506-514, 2013. [PubMed: 24011988] [Full Text: https://doi.org/10.1016/j.ajhg.2013.07.022]