橋小脳低形成

Pontocerebellar hypoplasia (PCH) is a group of inherited progressive neurodegenerative disorders with prenatal onset. Up to now ten different subtypes have been reported. All subtypes share common characteristics, including hypoplasia/atrophy of cerebellum and pons, progressive microcephaly, and variable cerebral involvement. Mutations in three tRNA splicing endonuclease subunit genes were found to be responsible for PCH2, PCH4 and PCH5. Mutations in the nuclear encoded mitochondrial arginyl- tRNA synthetase gene underlie PCH6. PCH1 is caused by homozygous mutation in the VRK1 gene.

先天奇形

(PCH1) VRK1 [HSA:7443] [KO:K08816]
(PCH1B) EXOSC3 [HSA:51010] [KO:K03681]
(PCH1C) EXOSC8 [HSA:11340] [KO:K12586]
(PCH2A/4/5) TSEN54 [HSA:283989] [KO:K15326]
(PCH2B) TSEN2 [HSA:80746] [KO:K15322]
(PCH2C) TSEN34 [HSA:79042] [KO:K15323]
(PCH2D) SEPSECS [HSA:51091] [KO:K03341]
(PCH2E) VPS53 [HSA:55275] [KO:K20299]
(PCH2F) TSEN15 [HSA:116461] [KO:K15324]
(PCH3) PCLO [HSA:27445] [KO:K16882]
(PCH6) RARS2 [HSA:57038] [KO:K01887]
(PCH7) TOE1 [HSA:114034] [KO:K13202]
(PCH8) CHMP1A [HSA:5119] [KO:K12197]
(PCH9) AMPD2 [HSA:271] [KO:K01490]
(PCH10) CLP1 [HSA:10978] [KO:K14399]

PMID:21749694

Namavar Y, Barth PG, Poll-The BT, Baas F

Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia.

Orphanet J Rare Dis 6:50 (2011)
DOI:10.1186/1750-1172-6-50

PMID:23564332

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EXOSC3 mutations in isolated cerebellar hypoplasia and spinal anterior horn involvement.

J Neurol 260:1866-70 (2013)
DOI:10.1007/s00415-013-6896-0

PMID:24989451

Boczonadi V, Muller JS, Pyle A, Munkley J, Dor T, Quartararo J, Ferrero I, Karcagi V, Giunta M, Polvikoski T, Birchall D, Princzinger A, Cinnamon Y, Lutzkendorf S, Piko H, Reza M, Florez L, Santibanez-Koref M, Griffin H, Schuelke M, Elpeleg O, Kalaydjieva L, Lochmuller H, Elliott DJ, Chinnery PF, Edvardson S, Horvath R

EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia.

Nat Commun 5:4287 (2014)
DOI:10.1038/ncomms5287

PMID:21368912

Namavar Y, Chitayat D, Barth PG, van Ruissen F, de Wissel MB, Poll-The BT, Silver R, Baas F

TSEN54 mutations cause pontocerebellar hypoplasia type 5.

Eur J Hum Genet 19:724-6 (2011)
DOI:10.1038/ejhg.2011.8

PMID:20920667

Agamy O, Ben Zeev B, Lev D, Marcus B, Fine D, Su D, Narkis G, Ofir R, Hoffmann C, Leshinsky-Silver E, Flusser H, Sivan S, Soll D, Lerman-Sagie T, Birk OS

Mutations disrupting selenocysteine formation cause progressive cerebello-cerebral atrophy.

Am J Hum Genet 87:538-44 (2010)
DOI:10.1016/j.ajhg.2010.09.007

PMID:24577744

Feinstein M, Flusser H, Lerman-Sagie T, Ben-Zeev B, Lev D, Agamy O, Cohen I, Kadir R, Sivan S, Leshinsky-Silver E, Markus B, Birk OS

VPS53 mutations cause progressive cerebello-cerebral atrophy type 2 (PCCA2).

J Med Genet 51:303-8 (2014)
DOI:10.1136/jmedgenet-2013-101823

PMID:27392077

Breuss MW, Sultan T, James KN, Rosti RO, Scott E, Musaev D, Furia B, Reis A, Sticht H, Al-Owain M, Alkuraya FS, Reuter MS, Abou Jamra R, Trotta CR, Gleeson JG

Autosomal-Recessive Mutations in the tRNA Splicing Endonuclease Subunit TSEN15 Cause Pontocerebellar Hypoplasia and Progressive Microcephaly.

Am J Hum Genet 99:228-35 (2016)
DOI:10.1016/j.ajhg.2016.05.023

PMID:25832664

Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A, Al-Turki S, Baple EL, Patton MA, Al-Memar AY, Hurles ME, Partlow JN, Hill RS, Evrony GD, Servattalab S, Markianos K, Walsh CA, Crosby AH, Mochida GH

Loss of PCLO function underlies pontocerebellar hypoplasia type III.

Neurology 84:1745-50 (2015)
DOI:10.1212/WNL.0000000000001523

PMID:28092684

Lardelli RM, Schaffer AE, Eggens VR, Zaki MS, Grainger S, Sathe S, Van Nostrand EL, Schlachetzki Z, Rosti B, Akizu N, Scott E, Silhavy JL, Heckman LD, Rosti RO, Dikoglu E, Gregor A, Guemez-Gamboa A, Musaev D, Mande R, Widjaja A, Shaw TL, Markmiller S, Marin-Valencia I, Davies JH, de Meirleir L, Kayserili H, Altunoglu U, Freckmann ML, Warwick L, Chitayat D, Blaser S, Caglayan AO, Bilguvar K, Per H, Fagerberg C, Christesen HT, Kibaek M, Aldinger KA, Manchester D, Matsumoto N, Muramatsu K, Saitsu H, Shiina M, Ogata K, Foulds N, Dobyns WB, Chi NC, Traver D, Spaccini L, Bova SM, Gabriel SB, Gunel M, Valente EM, Nassogne MC, Bennett EJ, Yeo GW, Baas F, Lykke-Andersen J, Gleeson JG

Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.

Nat Genet 49:457-464 (2017)
DOI:10.1038/ng.3762

PMID:23023333

Mochida GH, Ganesh VS, de Michelena MI, Dias H, Atabay KD, Kathrein KL, Huang HT, Hill RS, Felie JM, Rakiec D, Gleason D, Hill AD, Malik AN, Barry BJ, Partlow JN, Tan WH, Glader LJ, Barkovich AJ, Dobyns WB, Zon LI, Walsh CA

CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development.

Nat Genet 44:1260-4 (2012)
DOI:10.1038/ng.2425

PMID:23911318

Akizu N, Cantagrel V, Schroth J, Cai N, Vaux K, McCloskey D, Naviaux RK, Van Vleet J, Fenstermaker AG, Silhavy JL, Scheliga JS, Toyama K, Morisaki H, Sonmez FM, Celep F, Oraby A, Zaki MS, Al-Baradie R, Faqeih EA, Saleh MA, Spencer E, Rosti RO, Scott E, Nickerson E, Gabriel S, Morisaki T, Holmes EW, Gleeson JG

AMPD2 regulates GTP synthesis and is mutated in a potentially treatable neurodegenerative brainstem disorder.

Cell 154:505-17 (2013)
DOI:10.1016/j.cell.2013.07.005

PMID:24766809

Karaca E, Weitzer S, Pehlivan D, Shiraishi H, Gogakos T, Hanada T, Jhangiani SN, Wiszniewski W, Withers M, Campbell IM, Erdin S, Isikay S, Franco LM, Gonzaga-Jauregui C, Gambin T, Gelowani V, Hunter JV, Yesil G, Koparir E, Yilmaz S, Brown M, Briskin D, Hafner M, Morozov P, Farazi TA, Bernreuther C, Glatzel M, Trattnig S, Friske J, Kronnerwetter C, Bainbridge MN, Gezdirici A, Seven M, Muzny DM, Boerwinkle E, Ozen M, Clausen T, Tuschl T, Yuksel A, Hess A, Gibbs RA, Martinez J, Penninger JM, Lupski JR

Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.

Cell 157:636-50 (2014)
DOI:10.1016/j.cell.2014.02.058