#300919
Table of Contents
A number sign (#) is used with this entry because of evidence that X-linked intellectual developmental disorder-99 (XLID99) is caused by mutation in the USP9X gene (300072) on chromosome Xp11.
Heterozygous mutation in the USP9X gene can also cause female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F; 300968).
Homan et al. (2014) reported 4 patients from 3 unrelated families with X-linked recessive mental retardation. The families were previously ascertained by Tarpey et al. (2009) in a large-scale study that resequenced coding exons of the X chromosome in patients with mental retardation. The patients showed developmental delay, hypotonia, and some behavioral abnormalities, such as aggression. Two patients had broad thumbs and short stature; information on the other 2 patients was unavailable. One patient had relative macrocephaly, facial dysmorphism, constipation, and hyperextensible joints and skin. Brain MRI of 1 patient was normal.
The transmission pattern in 1 of the families with XLID99 reported by Homan et al. (2014) was consistent with X-linked recessive inheritance.
In affected male members of 2 unrelated families with X-linked recessive nonsyndromic intellectual developmental disorder-99, Homan et al. (2014) identified 2 different hemizygous mutations in the USP9X gene (L2093H; 300072.0001 and c.7574delA; 300072.0003). In 1 family, unaffected females were found to be heterozygous for the mutation. A patient from a third family carried a heterozygous USP9X variant (L2157I; 300072.0002), but he also carried a deletion including the ARID1B gene (614556), which is known to cause MRD12 (135900). None of the USP9X variants affected the catalytic activity of USP9X. Isolated hippocampal neurons from Usp9x-knockout male mice (-/Y) showed a 43% reduction in axonal length and arborization compared to wildtype. The 3 USP9X variants were unable to rescue the defect, consistent with a loss of function in axonal growth. Loss of Usp9x also caused a 42% decrease in neuronal migration, which was partially rescued by the L2093H variant, but not by L2157I or c.7574delA. The variants coimmunoprecipitated normally with DCX (300121) in nonpolarized HEK293 cells, but did not localize properly to the axonal growth cone in immature polarized neurons. Overall, the findings suggested that the USP9X variants caused changes in the neuronal cytoskeleton, which may affect neuronal migration and axonal growth, resulting in intellectual disability.
Homan, C. C., Kumar, R., Nguyen, L. S., Haan, E., Raymond, F. L., Abidi, F., Raynaud, M., Schwartz, C. E., Wood, S. A., Gecz, J., Jolly, L. A. Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth. Am. J. Hum. Genet. 94: 470-478, 2014. [PubMed: 24607389, images, related citations] [Full Text]
Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nature Genet. 41: 535-543, 2009. [PubMed: 19377476, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 777; DO: 0112026;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.4 | Intellectual developmental disorder, X-linked 99 | 300919 | X-linked recessive | 3 | USP9X | 300072 |
A number sign (#) is used with this entry because of evidence that X-linked intellectual developmental disorder-99 (XLID99) is caused by mutation in the USP9X gene (300072) on chromosome Xp11.
Heterozygous mutation in the USP9X gene can also cause female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F; 300968).
Homan et al. (2014) reported 4 patients from 3 unrelated families with X-linked recessive mental retardation. The families were previously ascertained by Tarpey et al. (2009) in a large-scale study that resequenced coding exons of the X chromosome in patients with mental retardation. The patients showed developmental delay, hypotonia, and some behavioral abnormalities, such as aggression. Two patients had broad thumbs and short stature; information on the other 2 patients was unavailable. One patient had relative macrocephaly, facial dysmorphism, constipation, and hyperextensible joints and skin. Brain MRI of 1 patient was normal.
The transmission pattern in 1 of the families with XLID99 reported by Homan et al. (2014) was consistent with X-linked recessive inheritance.
In affected male members of 2 unrelated families with X-linked recessive nonsyndromic intellectual developmental disorder-99, Homan et al. (2014) identified 2 different hemizygous mutations in the USP9X gene (L2093H; 300072.0001 and c.7574delA; 300072.0003). In 1 family, unaffected females were found to be heterozygous for the mutation. A patient from a third family carried a heterozygous USP9X variant (L2157I; 300072.0002), but he also carried a deletion including the ARID1B gene (614556), which is known to cause MRD12 (135900). None of the USP9X variants affected the catalytic activity of USP9X. Isolated hippocampal neurons from Usp9x-knockout male mice (-/Y) showed a 43% reduction in axonal length and arborization compared to wildtype. The 3 USP9X variants were unable to rescue the defect, consistent with a loss of function in axonal growth. Loss of Usp9x also caused a 42% decrease in neuronal migration, which was partially rescued by the L2093H variant, but not by L2157I or c.7574delA. The variants coimmunoprecipitated normally with DCX (300121) in nonpolarized HEK293 cells, but did not localize properly to the axonal growth cone in immature polarized neurons. Overall, the findings suggested that the USP9X variants caused changes in the neuronal cytoskeleton, which may affect neuronal migration and axonal growth, resulting in intellectual disability.
Homan, C. C., Kumar, R., Nguyen, L. S., Haan, E., Raymond, F. L., Abidi, F., Raynaud, M., Schwartz, C. E., Wood, S. A., Gecz, J., Jolly, L. A. Mutations in USP9X are associated with X-linked intellectual disability and disrupt neuronal cell migration and growth. Am. J. Hum. Genet. 94: 470-478, 2014. [PubMed: 24607389] [Full Text: https://doi.org/10.1016/j.ajhg.2014.02.004]
Tarpey, P. S., Smith, R., Pleasance, E., Whibley, A., Edkins, S., Hardy, C., O'Meara, S., Latimer, C., Dicks, E., Menzies, A., Stephens, P., Blow, M., and 67 others. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nature Genet. 41: 535-543, 2009. [PubMed: 19377476] [Full Text: https://doi.org/10.1038/ng.367]
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