| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16q22.1 | ?Methylmalonic aciduria and homocystinuria, cblL type | 620940 | Autosomal recessive | 3 | THAP11 | 609119 |
A number sign (#) is used with this entry because of evidence that methylmalonic aciduria and homocystinuria of the cblL type (MAHCL) is caused by homozygous mutation in the THAP11 gene (609119) on chromosome 16q11. One such patient has been reported.
Methylmalonic aciduria and homocystinuria of the cblL type (MAHCL) is an autosomal recessive metabolic disorder with onset of symptoms in infancy. The disorder is characterized by neurologic features, including seizures and profoundly impaired neurodevelopment. In the single reported patient, metabolic workup showed mild methylmalonicaciduria without homocystinuria, but complementation studies were consistent with a biochemical diagnosis of cblC (277400) and cblX (309541). Mutations in the MMACHC gene (609831) and HCFC1 (300019) were excluded before identification of mutation in the THAP11 gene (Quintana et al., 2017).
The biochemical abnormalities in cblC and cblX tend to be mild, and some patients with cblX without homocystinuria have been reported (Yu et al., 2013). Since THAP11 forms a functional complex with HCFC1, it is possible that future reported patients with THAP11 mutations may have homocystinuria (see review by Watkins and Rosenblatt, 2022).
Quintana et al. (2017) reported a boy, born of unrelated Moroccan parents, who presented at 2 months of age with myoclonic seizures followed by severely impaired global development. Metabolic workup showed mild methylmalonic aciduria and low-normal plasma methionine; homocysteine could not be detected in the urine. Later studies showed plasma homocysteine at the high end of normal. Standard treatment (protein restriction, hydroxocobalamin injection, pyridoxine, folic acid, and betaine) was ineffective. He gradually developed encephalopathy, tetraplegia, and profoundly impaired intellectual development. Eye examination showed esotropia and hyperopia. Brain imaging was not performed. The patient died from pneumonia at 10 years of age. Studies of patient fibroblasts showed impaired function of the cobalamin-dependent enzymes MUT (609058) and MTR (156570) and decreased synthesis of both adenosylcobalamin and methylcobalamin. Complementation studies were consistent with a biochemical diagnosis of cblC.
The transmission pattern of MAHCL in the family reported by Quintana et al. (2017) was consistent with autosomal recessive inheritance.
In a boy, born of Moroccan parents, with MAHCL, Quintana et al. (2017) identified a homozygous missense mutation in the THAP11 gene (F80L; 609119.0001). The mutation, which was found by direct sequencing of the THAP11 gene in patient cells, was not present in public databases, including gnomAD. Parental DNA was not available, so familial segregation studies could not be performed. Quintana et al. (2017) studied the THAP11 gene based on the known interaction between THAP11 and HCFC1 (300019), which is mutated in MAHCX (309541). Complementation studies were consistent with a biochemical diagnosis of cblC (277400); however, mutation in the MMACHC gene (609831) was excluded. RNA-seq analysis of patient fibroblasts showed downregulation of several genes, including TMOD2 (602928) and MMACHC, the latter of which most likely caused the aberrant cobalamin metabolism. The transcriptome clustered in the same clade found in patients with mutations in the HCFC1 gene. Retroviral transduction of MMACHC into patient THAP11 mutant fibroblasts corrected the cobalamin-related biochemical abnormalities. The findings, including results of studies in zebrafish (see ANIMAL MODEL), indicated that THAP11 and HCFC1 coregulate an overlapping set of genes which play a role in the phenotype of both MAHCL and MAHCX (309541).
Quintana et al. (2017) found that thap11-null zebrafish embryos had severe craniofacial abnormalities, including defective development of Meckel cartilage. These defects were restored with wildtype THAP11. Thap11-null zebrafish also showed structural brain anomalies associated with abnormal acetylated tubulin and reduced axons, as well as increased numbers of SOX2 (184429) neural progenitor cells, suggesting impaired neuronal differentiation. Overexpression of THAP11 mRNA also increased the number of SOX2-positive cells in certain brain regions. The results indicated that changes in the level of thap11 expression during brain development can alter the fate of neural precursors. In contrast, expression of the human F80L mutation (609119.0001) significantly decreased the number of SOX2-positive neural precursor cells in the developing brain, with a bias toward neuronal differentiation.
Chern et al. (2022) found that almost all mutant mice that were homozygous for the F80L mutation (609118.0001) died prior to weaning. Out of 260 mutant mice, only 1 survived to about 1 month of age and was runted. Studies of pregnant dams indicated that the homozygous mutant pups died from an inability to breathe, without brainstem, lung, or diaphragm defects. Mutant mice showed developmental brain defects and disrupted astrogliogenesis. Additional features included myocardial abnormalities, anemia, and craniofacial defects. F80L Thap11 mutant transcripts were increased in mutant mouse brain, but protein levels were decreased, suggesting instability of the mutant protein. Although mutant F80L Thap11 was still able to bind to Hcfc1, it likely was unable to bind to DNA, caused impaired function. There was a dramatic reduction in Mmachc RNA and protein expression associated with decreased cobalamin coenzymes MeCbl and AdoCbl and decreased functional activity of MTR and MUT. Similar findings were observed in hemizygous male mice carrying the HCFC1 mutation A115V (300019.0003). RNA-seq analysis showed dysregulation of genes involved in ribosome biogenesis and there was abnormal protein translation; the authors concluded that THAP11 and HCFC1 mutations cause a ribosomopathy.
Chern, T., Achilleos, A., Tong, X., Hill, M. C., Saltzman, A. B., Reineke, L. C., Chaudhury, A., Dasgupta, S. K., Redhead, Y., Watkins, D., Neilson, J. R., Thiagarajan, P., Green, J. B. A., Malovannaya, A., Martin, J. F., Rosenblatt, D. S., Poche, R. A. Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy. Nature Commun. 13: 134, 2022. [PubMed: 35013307] [Full Text: https://doi.org/10.1038/s41467-021-27759-7]
Quintana, A. M., Yu, H.-C., Brebner, A., Pupavac, M., Geiger, E. A., Watson, A., Castro, V. L., Cheung, W., Chen, S.-H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D. S., Shaikh, T. H. Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities. Hum. Molec. Genet. 26: 2838-2849, 2017. [PubMed: 28449119] [Full Text: https://doi.org/10.1093/hmg/ddx157]
Watkins, D., Rosenblatt, D. S. Inherited defects of cobalamin metabolism. Vitam. Horm. 119: 355-376, 2022. [PubMed: 35337626] [Full Text: https://doi.org/10.1016/bs.vh.2022.01.010]
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]