DO: 0080553; MONDO: 0014904;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q22.1 | ?Congenital disorder of glycosylation, type 1aa | 617082 | Autosomal recessive | 3 | NUS1 | 610463 |
A number sign (#) is used with this entry because of evidence that congenital disorder of glycosylation type Iaa (CDG1AA) is caused by homozygous mutation in the NUS1 gene (610463) on chromosome 6q22. One such family has been reported.
For a general discussion of CDGs, see CDG1A (212065).
Park et al. (2014) reported 2 sibs, born of unrelated Czech Roma parents, with a severe neurodevelopmental disorder apparent since birth. The patients had generalized hypotonia, profound developmental delay, and early-onset refractory seizures with regression. Other features included failure to thrive, small head, spasticity, and congenital scoliosis. One child died at age 29 months. Postmortem examination showed nonspecific neuronal loss in the brain cortex and cerebellum. The other patient had central visual and hearing impairment and mottling of the retinal pigment epithelium. Repeat eye examination at age 4 years showed macular lesions with foveal hyperautofluorescence. He had no social interaction, no spontaneous movements, and marked hypertrichosis. Brain imaging showed severe cortical atrophy. Routine laboratory tests were unremarkable, and cholesterol levels were normal.
The transmission pattern of CDG1AA in the family reported by Park et al. (2014) was consistent with autosomal recessive inheritance.
In 2 sibs, born of unrelated Czech parents with CDG1AA, Park et al. (2014) identified a homozygous missense mutation in the NUS1 gene (R290H; 610463.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found in the heterozygous state in 2 of 255 individuals of Roma origin. Patient fibroblasts showed normal expression of the mutant protein, but mutant cells showed increased accumulation of free cholesterol similar to cells in which NUS1 was silenced. In addition, cis-PTase activity and mannose incorporation into proteins was markedly decreased in patient fibroblasts compared to controls, consistent with impaired NUS1 function. Western blot analysis of patient fibroblasts showed hypoglycosylation of LAMP1 (153330) and ICAM1 (147840). All mutation carriers had altered dolichol profiles in the urine and serum compared to controls.
Park et al. (2014) found that complete knockdown of the Nus1 gene in mice was embryonic lethal before E6.5, indicating postimplantation lethality. Mouse embryonic fibroblasts with conditional knockdown of the Nus1 allele showed accumulation of free cholesterol, decreased cis-PTase activity, and decreased mannose incorporation into protein. Mutant fibroblasts showed decreased viability in response to treatment with an HMG-CoA reductase inhibitor compared to controls. In addition, the cells showed activation of the unfolded protein response pathway of ER stress.
Park, E. J., Grabinska, K. A., Guan, Z., Stranecky, V., Hartmannova, H., Hodanova, K., Baresova, V., Sovova, J., Jozsef, L., Ondruskova, N., Hansikova, H., Honzik, T., Zeman, J., Hulkova, H., Wen, R., Kmoch, S., Sessa, W. C. Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation. Cell Metab. 20: 448-457, 2014. [PubMed: 25066056] [Full Text: https://doi.org/10.1016/j.cmet.2014.06.016]