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. 2018 Jul 25;99(2):302-314.e4.
doi: 10.1016/j.neuron.2018.06.019. Epub 2018 Jul 5.

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus

Charuta Gavankar Furey  1 , Jungmin Choi  2 , Sheng Chih Jin  2 , Xue Zeng  2 , Andrew T Timberlake  2 , Carol Nelson-Williams  2 , M Shahid Mansuri  3 , Qiongshi Lu  4 , Daniel Duran  3 , Shreyas Panchagnula  3 , August Allocco  3 , Jason K Karimy  3 , Arjun Khanna  5 , Jonathan R Gaillard  3 , Tyrone DeSpenza  3 , Prince Antwi  3 , Erin Loring  2 , William E Butler  5 , Edward R Smith  6 , Benjamin C Warf  6 , Jennifer M Strahle  7 , David D Limbrick  7 , Phillip B Storm  8 , Gregory Heuer  8 , Eric M Jackson  9 , Bermans J Iskandar  10 , James M Johnston  11 , Irina Tikhonova  12 , Christopher Castaldi  12 , Francesc López-Giráldez  12 , Robert D Bjornson  12 , James R Knight  13 , Kaya Bilguvar  12 , Shrikant Mane  12 , Seth L Alper  14 , Shozeb Haider  15 , Bulent Guclu  16 , Yasar Bayri  17 , Yener Sahin  17 , Michael L J Apuzzo  3 , Charles C Duncan  3 , Michael L DiLuna  3 , Murat Günel  1 , Richard P Lifton  18 , Kristopher T Kahle  19
Affiliations

De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus

Charuta Gavankar Furey et al. Neuron. .

Abstract

Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 × 10-7), SMARCC1 (p = 8.15 × 10-10), and PTCH1 (p = 1.06 × 10-6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 × 10-4). Together, these probands account for ∼10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.

Keywords: PTCH1; SHH; SMARCC1; TRIM71; aqueductal stenosis; congenital hydrocephalus; de novo variants; gene discovery; neural stem cell; whole-exome sequencing.

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Conflict of interest statement

DECLARATION OF INTERESTS

The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Recurrent, Identical De Novo Mutations in LIN-41/TRIM71 Encoding the let-7 miRNA Target TRIM71
(A) Representative sagittal (left) and axial (right) brain magnetic resonance images of CH probands Hydro100–1 and Hydro102–5 show communicating hydrocephalus. (B) Pedigrees with Sanger-verified mutated bases (red) and the corresponding wild-type bases marked on the chromatograms. (C) Structural modeling of TRIM71 mutation impact. The positively charged guanidinium side chain of p.Arg796 interacts with the negatively charged sugar-phosphate backbone of target RNAs to aid in maintaining the spatial position of the nucleic acid. Mutation of this p.Arg796 residue to the imidazole ring of histidine (ΔΔG = 2.0 kcal/mol) is predicted to disrupt this interaction (right). The side chain of p.Arg608 makes hydrogen bonds with uracil in target RNAs. The p.Arg608His mutation (ΔΔG = 1.6 kcal/mol) is predicted to disrupt these hydrogen bonds (left). (D) Mapping of TRIM71 mutations. p.Arg608His and p.Arg796His affect conserved residues in the 16th position of the respective 1st and 5th blades of TRIM71’s NHL domain, which mediates the binding of target RNA. (E) In situ hybridization of wild-type E12.5 and adult mouse brains for Trim71 showing signals in the ciliated neuroepithelium and ventricular zone (V, ventricle; arrow, neuroepithelium at E12.5 and ependymal layer in adulthood; 2.5× and 10× magnification).
Figure 2.
Figure 2.. De Novo and Transmitted Mutations in SMARCC1 Encoding the SWI/SNF Chromatin Modifier BAF155
(A) Representative sagittal (left) and coronal (right) brain magnetic resonance images of CH probands Hydro106–1 and Hydro108–1 with obstructive hydrocephalus.. (B) Pedigrees with Sanger-verified mutated bases and the corresponding normal alleles marked on the chromatograms.. (C) In situ hybridization of wild-type E12.5 and adult mouse brains for Smarcc1 showing signals in the ciliated neuroepithelium and ventricular zone (V, ventricle; arrow, neuroepithelium at E12.5, 2.5×, and ependymal layer in adulthood; 10× magnification).
Figure 3.
Figure 3.. De Novo and Transmitted Mutations in PTCH1 Encoding the Sonic Hedgehog Receptor Patched-1
(A) Representative sagittal (left) and axial (right) brain magnetic resonance images of CH probands Hydro103–1 and Hydro104–1 with obstructive hydrocephalus.. (B) Pedigrees with Sanger-verified mutated bases and the corresponding normal alleles marked on the chromatograms.. (C) In situ hybridization of wild-type E12.5 and adult mouse brains for Ptch1 demonstrates expression in the hindbrain neuroepithelium (V, ventricle; arrow, neuroepithelium at E12.5, 2.5×, and ependymal layer in adulthood; 10× magnification).
Figure 4.
Figure 4.. Meta-analysis of Rare De Novo and Transmitted Mutations in Mutation-Intolerant Genes
Quantile-quantile plot of observed versus expected p values from meta-analysis of protein-altering de novo and LOF transmitted heterozygous variants comparing the burden of rare variants in genes intolerant to LOF mutation (pLI ≥ 0.90, MAF ≤ 2 × 10−5).
See this image and copyright information in PMC

Comment in

References

    1. Adle-Biassette H, Saugier-Veber P, Fallet-Bianco C, Delezoide A-L, Razavi F, Drouot N, Bazin A, Beaufrère A-M, Bessières B, Blesson S, et al. (2013). Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases. Acta Neuropathol. 126, 427–442. - PubMed
    1. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, and Sunyaev SR (2010). A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249. - PMC - PubMed
    1. Aeschimann F, Kumari P, Bartake H, Gaidatzis D, Xu L, Ciosk R, and Großhans H (2017). LIN41 post-transcriptionally silences mRNAs by two distinct and position-dependent mechanisms. Mol. Cell 65, 476–489.e4. - PubMed
    1. Al-Dosari MS, Al-Owain M, Tulbah M, Kurdi W, Adly N, Al-Hemidan A, Masoodi TA, Albash B, and Alkuraya FS (2013). Mutation in MPDZ causes severe congenital hydrocephalus. J. Med. Genet 50, 54–58. - PubMed
    1. Allache R, Lachance S, Guyot MC, De Marco P, Merello E, Justice MJ, Capra V, and Kibar Z (2014). Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway. Hum. Mol. Genet 23, 1687–1699. - PMC - PubMed

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