Mutations Cause a Novel Syndrome Characterized by Ataxia and Mild Mental Retardation with Predisposition to Quadrupedal Gait

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We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans.

Vyšlo v časopise: Mutations Cause a Novel Syndrome Characterized by Ataxia and Mild Mental Retardation with Predisposition to Quadrupedal Gait. PLoS Genet 5(5): e32767. doi:10.1371/journal.pgen.1000487
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000487

Souhrn

Zdroje

1. SchölsL

BauerP

SchmidtT

SchulteT

RiessO

2004 Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 3 291 304

2. FogelBL

PerlmanS

2007 Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol 6 245 257

3. BoycottKM

FlavelleS

BureauA

GlassHC

FujiwaraTM

2005 Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. Am J Hum Genet 77 477 483

4. OzcelikT

AkarsuN

UzE

CaglayanS

GulsunerS

2008 Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc Natl Acad Sci USA 105 4232 4236

5. TürkmenS

HoffmannK

DemirhanO

AruobaD

HumphreyN

2008 Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene. Eur J Hum Genet 16 1070 1074

6. MohebLA

TzschachA

GarshasbiM

KahriziK

DarvishH

2008 Identification of a nonsense mutation in the very low-density lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome. Eur J Hum Genet 16 270 273

7. TürkmenS

DemirhanO

HoffmannK

DiersA

ZimmerC

2006 Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p. J Med Genet 43 461 464

8. SkoylesJR

2006 Human balance, the evolution of bipedalism and dysequilibrium syndrome. Medical Hypotheses 66 1060 1068

9. RobinsonPN

KöhlerS

BauerS

SeelowD

HornD

2008 The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. Am J Hum Genet 83 610 615

10. TaniuchiK

NishimoriI

TakeuchiT

OhtsukiY

OnishiS

2002 cDNA cloning and developmental expression of murine carbonic anhydrase-related proteins VIII, X, and XI. Brain Res Mol Brain Res 109 207 215

11. SjöblomB

EllebyB

WallgrenK

JonssonBH

LindskogS

1996 Two point mutations convert a catalytically inactive carbonic anhydrase-related protein (CARP) to an active enzyme. FEBS Lett 398 322 325

12. JiaoY

YanJ

ZhaoY

DonahueLR

BeamerWG

2005 Carbonic anhydrase-related protein VIII deficiency is associated with a distinctive lifelong gait disorder in waddles mice. Genetics 171 1239 1246

13. HirasawaM

XuX

TraskRB

MaddatuTP

JohnsonBA

2007 Carbonic anhydrase related protein 8 mutation results in aberrant synaptic morphology and excitatory synaptic function in the cerebellum. Mol Cell Neurosci 35 161 170

14. CavalierL

OuahchiK

KaydenHJ

Di DonatoS

ReutenauerL

1998 Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet 62 301 310

15. HirotaJ

AndoH

HamadaK

MikoshibaK

2003 Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5-trisphosphate receptor type 1. Biochem J 372 435 441

16. HurEM

ParkY-S

HuhYH

YooSH

WooK-C

2005 Junctional membrane inositol 1,4,5-trisphosphate receptor complex coordinates sensitization of the silent EGF-induced Ca2+ signaling. J Cell Biol 169 657 667

17. van de LeemputJ

ChandranJ

KnightA

HoltzclawLA

ScholzS

2007 Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet 3 e108

18. ChenX

TangTS

TuH

NelsonO

PookM

2008 Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3. J Neurosci 28 12713 12724

19. PattersonRL

BoehningD

SnyderSH

2004 Inositol 1,4,5-trisphosphate receptors as signal integrators. Annu Rev Biochem 73 437 465

20. HirasawaM

XuX

TraskRB

MaddatuTP

JohnsonBA

2007 Carbonic anhydrase related protein 8 mutation results in aberrant synaptic morphology and excitatory synaptic function in the cerebellum. Mol Cell Neurosci 35 161 170

21. MatsumotoM

NakagawaT

InoueT

NagataE

TanakaK

1996 Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-trisphosphate receptor. Nature 379 168 171

22. AibaA

KanoM

ChenC

StantonME

FoxGD

1994 Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell 79 377 388

23. WangZ

MoultJ

2001 SNPs, protein structure, and disease. Hum Mutat 17 263 270

24. HumphreyN

MundlosS

TürkmenS

2008 Genes and quadrupedal locomotion in humans. Proc Natl Acad Sci U S A 105 E26

25. JoubertM

EisenringJJ

RobbJP

AndermannF

1969 Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 19 813 825

26. KruglyakL

DalyMJ

Reeve-DalyMP

LanderES

1996 Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58 1347 1363

27. GudbjartssonDF

JonassonK

FriggeML

KongA

2000 Allegro, a new computer program for multipoint linkage analysis. Nat Genet 25 12 13

28. AbecasisGR

ChernySS

CooksonWO

CardonLR

2002 Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30 97 101

29. LindnerTH

HoffmannK

2005 easyLINKAGE: A PERL script for easy and automated two-/multi-point linkage analyses. Bioinformatics 21 405 407

30. HoffmannK

LindnerTH

2005 easyLINKAGE-Plus–automated linkage analyses using large-scale SNP data. Bioinformatics 21 3565 3567

31. BoomsP

TieckeF

RosenbergT

HagemeierC

RobinsonPN

2000 Differential effect of FBN1 mutations on in vitro proteolysis of recombinant fibrillin-1 fragments. Hum Genet 107 216 224

32. BoomsP

NeyA

BarthelF

MoroyG

CounsellD

2006 A fibrillin-1-fragment containing the elastin-binding-protein GxxPG consensus sequence upregulates matrix metalloproteinase-1: biochemical and computational analysis. J Mol Cell Cardiol 40 234 246

33. AbramoffMD

MagelhaesPJ

RamSJ

2004 Image processing with ImageJ. Biophotonics International 11 36 42

34. ThompsonJD

GibsonTJ

HigginsDG

2002 Multiple sequence alignment using ClustalW and ClustalX. Curr Protoc Bioinformatics Chapter 2:Unit 2.3

35. BeitzE

2000 TEXshade: shading and labeling of multiple sequence alignments using LATEX2ε. Bioinformatics 16 135 139