NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation
- Baylor College of Medicine, United States
- Texas Children's Hospital, United States
- Cleveland Clinic Children's Hospital, United States
- University of Tennessee Health Science Center, United States
- Instituto Nacional de Saude da Mulher, da Criança e do Adolescente Fernandes Figueira, Brazil
- Howard Hughes Medical Institute, Baylor College of Medicine, United States
Figures
Figure 1
Subjects with NUDT21-spanning copy-number variations (CNVs).
(A) Five intrachromosomal rearrangements of chromosome 16q including the NUDT21 gene, identified by clinical array comparative genomic hybridization. Duplications shown in blue, deletion in red. …
Figure 2 with 1 supplement
CFIm25 regulates MeCP2 protein levels in patient-derived lymphoblastoid cells with NUDT21 CNVs.
(A) Representative western blot picture for three duplication patients compared to four age-matched controls showing the increase of CFIm25 and decrease of MeCP2 protein levels. (B) Representative …
Figure 2—figure supplement 1
siGLO nucleofection showing patient-derived lymphoblastoid cells can be transfected with small RNA.
(A) Representative histograms of control (i) and siGLO-nucleofected lymphoblastoid cells showing nearly 100% efficiency using both the functionality (ii) and efficiency (iii) protocols. (B) Time …
Figure 3 with 2 supplements
NUDT21 mRNA levels correlate with inefficiently translated long MECP2 mRNA.
(A) RNA quantification by quantitative RT-polymerase chain reaction (qRT-PCR) from lymphoblastoid cells of NUDT21 duplication and deletion patients. The bar graph shows the total mRNA fold change of …
Figure 3—figure supplement 1
Northern blot assay from patient-derived lymphoblastoid cells.
Northern blot assay of lymphoblastoid cells showing that duplication (left panel) and deletion (right panel) patients respectively have more long or short MECP2 3′ UTR isoforms. Relative northern …
Figure 3—figure supplement 2
Polyribosome fractionation traces of control and duplication subjects.
Representative polyribosome traces from control (A-C) and duplication (D-F) subjects. UV absorption at 254 nm was plotted vs time depicting the successful resolution of the different ribosomal …
Author response image 1
Northern blot assay from patient-derived lymphoblast cells.
Northern blot assay showing that duplication and deletion patients respectively have more long or short MECP2 isoforms (left panel). Quantification of three duplication patients and one deletion …
Tables
Table 1
Molecular and clinical characteristics of four individuals with NUDT21 duplication and one individual with NUDT21 deletion
| Subject 1 | Subject 2 | Subject 3 | Subject 4 | Subject 5 | |
|---|---|---|---|---|---|
| Sex | F | M | M | F | F |
| Age | 10 years | 5 years | 15 years | 13 years | 8 years |
| Deletion/duplication | Duplication | Duplication | Duplication | Deletion | Duplication |
| Coordinates | chr16: 46,500,741-64,653,093 | chr16: 46,500,741-58,539,422 | chr16: 55,725,264-57,533,101 | chr16: 56,344,856-63,521,523 | chr16: 55,919,145-56,619,283 |
| Size | 18.15 Mb | 12.04 Mb | 1.81 Mb | 7.18 Mb | 0.70 Mb |
| Zygosity | Heterozygous | Heterozygous | Mosaic marker chromosome (present in 45% of cells) | Heterozygous | Heterozygous |
| Inheritance | De novo | De novo | De novo | Unknown | Not maternal* |
| Additional CNVs | 52 kb duplication of chr6: 152, 716, 341-152, 768, 421 (maternal) | None | None | 144 kb duplication of chr17: 427, 284-571, 275 (inheritance unknown) | None |
| Developmental delay/intellectual disability | Intellectual disability (clinical impression: moderate) | Significant developmental delay | Intellectual disability | Intellectual disability (full scale IQ 53) | Intellectual disability |
| Developmental regression | Yes, at 2 years of age | No | Yes | No | No |
| Autism spectrum disorder | Yes | No | Yes | No | Yes |
| Epilepsy | Single, isolated seizure at 5 years of age | No | No | Intractable, symptomatic partial onset seizures | No |
| ADHD | Yes | Yes | Unknown | Yes | No |
-
F, female; M, male; chr, chromosome; MB, megabases; CNVs, copy number variants; kb, kilobases; ADHD, attention deficit hyperactivity disorder.
-
*
Father not available.
