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CC2D1A regulates human intellectual and social function as well as NF-κB signaling homeostasis.

Manzini MC, Xiong L, Shaheen R, Tambunan DE, Di Costanzo S, Mitisalis V, Tischfield DJ, Cinquino A, Ghaziuddin M, Christian M, Jiang Q, Laurent S, Nanjiani ZA, Rasheed S, Hill RS, Lizarraga SB, Gleason D, Sabbagh D, Salih MA, Alkuraya FS, Walsh CA - Cell Rep (2014)

Bottom Line: CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB).Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling.Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.

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CC2D1A Null Mutations Cause Severe ID, ASD, and Seizures(A) Four families with 16 individuals affected with ID and ASD plus seizures. Affected individuals are represented by shaded symbols (squares indicate males; circles indicate females). Fam, family.(B) All individuals in families 1, 2, and 3 carried a splicing mutation at the junction of exon and intron 6 of CC2D1A (see gene schematic). Individuals in family 4 carried a 1 bp deletion in exon 3 leading to a frameshift in the coding sequence.(C) The splicing mutation causes complete skipping of exon 6 as shown by RT-PCR analysis of cDNA from patient cell lines. NA, not affected; aff, affected.(D) The protein change p.T172Vfs*51 is predicted to generate a 223 amino acid truncated protein that could not be found by western blot in cell lines from an affected individual, a parent (NA het), and a normal control (NA).(E) Schematic representation of the predicted protein fragments generated by the identified mutations. In all cases, mutations are predicted to generate a complete loss-of-function phenotype.
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Figure 1: CC2D1A Null Mutations Cause Severe ID, ASD, and Seizures(A) Four families with 16 individuals affected with ID and ASD plus seizures. Affected individuals are represented by shaded symbols (squares indicate males; circles indicate females). Fam, family.(B) All individuals in families 1, 2, and 3 carried a splicing mutation at the junction of exon and intron 6 of CC2D1A (see gene schematic). Individuals in family 4 carried a 1 bp deletion in exon 3 leading to a frameshift in the coding sequence.(C) The splicing mutation causes complete skipping of exon 6 as shown by RT-PCR analysis of cDNA from patient cell lines. NA, not affected; aff, affected.(D) The protein change p.T172Vfs*51 is predicted to generate a 223 amino acid truncated protein that could not be found by western blot in cell lines from an affected individual, a parent (NA het), and a normal control (NA).(E) Schematic representation of the predicted protein fragments generated by the identified mutations. In all cases, mutations are predicted to generate a complete loss-of-function phenotype.

Mentions: We report 4 families with a total of 16 individuals affected by a spectrum of cognitive and social impairments, including ASD, nonsyndromic ID (NSID), and seizures (Figure 1A). Families 1 and 2 represent two related consanguineous families from Saudi Arabia. In family 1, one male is affected by ASD and ID (individual 1:4), one male by cognitive problems and aggressive behavior (1:1), and two females by moderate-to-severe NSID (1:2 and 1:3). In family 2, two males (2:1 and 2:2) and one female (2:3) are affected by combinations of ASD, severe NSID, language impairment, and seizures (Table S1 for clinical information). The parents in family 3 are first cousins once removed, also from Saudi Arabia, and four siblings (three males and one female) are affected by severe NSID with language impairment (Table S1). Finally, five Pakistani males with variable presentation belonged to family 4: individuals 4:1, 4:2, and 4:4 had moderate NSID, individual 4:3 was more severely affected with language impairment and borderline autistic features, and individual 4:5 had moderate ASD/ID (Table S1). The parents reported being unrelated.


CC2D1A regulates human intellectual and social function as well as NF-κB signaling homeostasis.

Manzini MC, Xiong L, Shaheen R, Tambunan DE, Di Costanzo S, Mitisalis V, Tischfield DJ, Cinquino A, Ghaziuddin M, Christian M, Jiang Q, Laurent S, Nanjiani ZA, Rasheed S, Hill RS, Lizarraga SB, Gleason D, Sabbagh D, Salih MA, Alkuraya FS, Walsh CA - Cell Rep (2014)

CC2D1A Null Mutations Cause Severe ID, ASD, and Seizures(A) Four families with 16 individuals affected with ID and ASD plus seizures. Affected individuals are represented by shaded symbols (squares indicate males; circles indicate females). Fam, family.(B) All individuals in families 1, 2, and 3 carried a splicing mutation at the junction of exon and intron 6 of CC2D1A (see gene schematic). Individuals in family 4 carried a 1 bp deletion in exon 3 leading to a frameshift in the coding sequence.(C) The splicing mutation causes complete skipping of exon 6 as shown by RT-PCR analysis of cDNA from patient cell lines. NA, not affected; aff, affected.(D) The protein change p.T172Vfs*51 is predicted to generate a 223 amino acid truncated protein that could not be found by western blot in cell lines from an affected individual, a parent (NA het), and a normal control (NA).(E) Schematic representation of the predicted protein fragments generated by the identified mutations. In all cases, mutations are predicted to generate a complete loss-of-function phenotype.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4334362&req=5

Figure 1: CC2D1A Null Mutations Cause Severe ID, ASD, and Seizures(A) Four families with 16 individuals affected with ID and ASD plus seizures. Affected individuals are represented by shaded symbols (squares indicate males; circles indicate females). Fam, family.(B) All individuals in families 1, 2, and 3 carried a splicing mutation at the junction of exon and intron 6 of CC2D1A (see gene schematic). Individuals in family 4 carried a 1 bp deletion in exon 3 leading to a frameshift in the coding sequence.(C) The splicing mutation causes complete skipping of exon 6 as shown by RT-PCR analysis of cDNA from patient cell lines. NA, not affected; aff, affected.(D) The protein change p.T172Vfs*51 is predicted to generate a 223 amino acid truncated protein that could not be found by western blot in cell lines from an affected individual, a parent (NA het), and a normal control (NA).(E) Schematic representation of the predicted protein fragments generated by the identified mutations. In all cases, mutations are predicted to generate a complete loss-of-function phenotype.
Mentions: We report 4 families with a total of 16 individuals affected by a spectrum of cognitive and social impairments, including ASD, nonsyndromic ID (NSID), and seizures (Figure 1A). Families 1 and 2 represent two related consanguineous families from Saudi Arabia. In family 1, one male is affected by ASD and ID (individual 1:4), one male by cognitive problems and aggressive behavior (1:1), and two females by moderate-to-severe NSID (1:2 and 1:3). In family 2, two males (2:1 and 2:2) and one female (2:3) are affected by combinations of ASD, severe NSID, language impairment, and seizures (Table S1 for clinical information). The parents in family 3 are first cousins once removed, also from Saudi Arabia, and four siblings (three males and one female) are affected by severe NSID with language impairment (Table S1). Finally, five Pakistani males with variable presentation belonged to family 4: individuals 4:1, 4:2, and 4:4 had moderate NSID, individual 4:3 was more severely affected with language impairment and borderline autistic features, and individual 4:5 had moderate ASD/ID (Table S1). The parents reported being unrelated.

Bottom Line: CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB).Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling.Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity.

View Article: PubMed Central - PubMed

Affiliation: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.

Show MeSH
Related in: MedlinePlus