Polyalanine tract disorders and neurocognitive phenotypes.

Expansion of polyalanine tracts cause at least 9 inherited human diseases. Eight of these nine diseases are due to expansions in transcription factors and give rise to congenital disorders, many with neurocognitive phenotypes. Disease-causing expansions vary in length dependingupon the gene in question, with the severity of the associated clinical phenotype generally increasing with length of the polyalanine tract. The past decade has seen considerable progress in the understanding on how these mutations may arise and the functional effect of expanded polyalanine tracts on the resulting protein. Despite this progress, the pathogenic mechanism of expanded polyalanine tracts contributing to the associated disease states remains poorly understood. Gaining insights into the mechanisms that underlie the pathogenesis of different expanded polyalanine tract mutations will be a necessary step on the path to the design of potential treatment strategies for the associated diseases.

[1]  J. Gécz,et al.  Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation. , 2002, American journal of medical genetics.

[2]  Shinji Saitoh,et al.  A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome). , 2007, American journal of human genetics.

[3]  B. Brais,et al.  Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA. , 2000, Human molecular genetics.

[4]  R. Veitia,et al.  A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction , 2006, Human Genetics.

[5]  J. Rommens,et al.  Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy , 1998, Nature Genetics.

[6]  Tomohiko Nakamura,et al.  Molecular analysis of congenital central hypoventilation syndrome , 2003, Human Genetics.

[7]  K. Devriendt,et al.  Spectrum of FOXL2 gene mutations in blepharophimosis-ptosis-epicanthus inversus (BPES) families demonstrates a genotype--phenotype correlation. , 2001, Human molecular genetics.

[8]  J. Bag,et al.  Induction of HSP70 expression and recruitment of HSC70 and HSP70 in the nucleus reduce aggregation of a polyalanine expansion mutant of PABPN1 in HeLa cells. , 2005, Human molecular genetics.

[9]  J. Gécz,et al.  Three new families with X‐linked mental retardation caused by the 428–451dup(24bp) mutation in ARX , 2004, Clinical genetics.

[10]  A. Munnich,et al.  Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome , 2003, Nature Genetics.

[11]  J. Golden,et al.  A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death , 2004, The Journal of cell biology.

[12]  P. Robinson,et al.  A molecular pathogenesis for transcription factor associated poly-alanine tract expansions. , 2004, Human molecular genetics.

[13]  D. Schlessinger,et al.  The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome , 2001, Nature Genetics.

[14]  A. Munnich,et al.  Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. , 2005, Human molecular genetics.

[15]  Richard C Trembath,et al.  Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E. , 2003, American journal of human genetics.

[16]  S. Mundlos,et al.  Mutant Hoxd13 induces extra digits in a mouse model of synpolydactyly directly and by decreasing retinoic acid synthesis. , 2008, The Journal of clinical investigation.

[17]  The pattern of inheritance of X‐linked traits is not dominant or recessive, just X‐linked , 2006 .

[18]  R. Ravazzolo,et al.  Distinct pathogenetic mechanisms for PHOX2B associated polyalanine expansions and frameshift mutations in congenital central hypoventilation syndrome. , 2005, Human molecular genetics.

[19]  P. Scambler,et al.  Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13 , 2002, Journal of medical genetics.

[20]  D. Duboule,et al.  The mouse Hoxd13(spdh) mutation, a polyalanine expansion similar to human type II synpolydactyly (SPD), disrupts the function but not the expression of other Hoxd genes. , 2001, Developmental biology.

[21]  D. Wieczorek,et al.  Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. , 2001, Human molecular genetics.

[22]  B. Brais,et al.  Involvement of the ubiquitin-proteasome pathway and molecular chaperones in oculopharyngeal muscular dystrophy. , 2003, Human molecular genetics.

[23]  M. Owen,et al.  Mutations Involving the Transcription Factor CBFA1 Cause Cleidocranial Dysplasia , 1997, Cell.

[24]  Y. Hérault,et al.  Fork Stalling and Template Switching As a Mechanism for Polyalanine Tract Expansion Affecting the DYC Mutant of HOXD13, a New Murine Model of Synpolydactyly , 2009, Genetics.

[25]  J. Frost,et al.  A Triplet Repeat Expansion Genetic Mouse Model of Infantile Spasms Syndrome, Arx(GCG)10+7, with Interneuronopathy, Spasms in Infancy, Persistent Seizures, and Adult Cognitive and Behavioral Impairment , 2009, The Journal of Neuroscience.

[26]  R. Ravazzolo,et al.  PHOX2B mutations and polyalanine expansions correlate with the severity of the respiratory phenotype and associated symptoms in both congenital and late onset Central Hypoventilation syndrome , 2004, Journal of Medical Genetics.

[27]  J. Gécz,et al.  A novel de novo 27 bp duplication of the ARX gene, resulting from postzygotic mosaicism and leading to three severely affected males in two generations , 2009, American journal of medical genetics. Part A.

[28]  G. Rouleau,et al.  Molecular mechanisms underlying polyalanine diseases , 2009, Neurobiology of Disease.

[29]  R M Winter,et al.  Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[30]  I. Scheffer,et al.  X-linked myoclonic epilepsy with spasticity and intellectual disability: Mutation in the homeobox gene ARX , 2002, Neurology.

[31]  S. Mundlos,et al.  The other trinucleotide repeat: polyalanine expansion disorders. , 2005, Current opinion in genetics & development.

[32]  J. Lupski,et al.  Mechanisms for human genomic rearrangements , 2008, PathoGenetics.

[33]  E. Eichler,et al.  Length of uninterrupted CGG repeats determines instability in the FMR1 gene , 1994, Nature Genetics.

[34]  S. Mundlos,et al.  Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model. , 2004, Human molecular genetics.

[35]  J. Gécz,et al.  ARX: a gene for all seasons. , 2006, Current opinion in genetics & development.

[36]  R. Ravazzolo,et al.  Geldanamycin promotes nuclear localisation and clearance of PHOX2B misfolded proteins containing polyalanine expansions. , 2007, The international journal of biochemistry & cell biology.

[37]  R. Veitia,et al.  Missense mutations in the forkhead domain of FOXL2 lead to subcellular mislocalization, protein aggregation and impaired transactivation. , 2008, Human molecular genetics.

[38]  J. Opitz,et al.  A 72‐year‐old Danish puzzle resolved—comparative analysis of phenotypes in families with different‐sized HOXD13 polyalanine expansions , 2005, American journal of medical genetics. Part A.

[39]  R. Veitia,et al.  Differential aggregation and functional impairment induced by polyalanine expansions in FOXL2, a transcription factor involved in cranio-facial and ovarian development. , 2007, Human molecular genetics.

[40]  L. Thompson,et al.  Therapeutic application of histone deacetylase inhibitors for central nervous system disorders , 2008, Nature Reviews Drug Discovery.

[41]  R. Veitia,et al.  A recurrent polyalanine expansion in the transcription factor FOXL2 induces extensive nuclear and cytoplasmic protein aggregation , 2004, Journal of Medical Genetics.

[42]  Y. Yanagawa,et al.  Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice. , 2009, Human molecular genetics.

[43]  P. Thomas,et al.  Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency. , 2002, American journal of human genetics.

[44]  S. Mundlos,et al.  Altered Growth and Branching Patterns in Synpolydactyly Caused by Mutations in HOXD13 , 1996, Science.

[45]  P. Scambler,et al.  Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. , 2000, American journal of human genetics.

[46]  M. Lentze,et al.  A novel stable polyalanine [poly(A)] expansion in the HOXA13 gene associated with hand-foot-genital syndrome: proper function of poly(A)-harbouring transcription factors depends on a critical repeat length? , 2002, Human Genetics.

[47]  M. Sarfarazi,et al.  Genomic structure of HOXD13 gene: a nine polyalanine duplication causes synpolydactyly in two unrelated families. , 1996, Human molecular genetics.

[48]  Mark F Bear,et al.  The mGluR theory of fragile X mental retardation , 2004, Trends in Neurosciences.

[49]  Osamu Onodera,et al.  Polyglutamine diseases: where does toxicity come from? what is toxicity? where are we going? , 2010, Journal of molecular cell biology.

[50]  B. Benayoun,et al.  Towards a functional classification of pathogenic FOXL2 mutations using transactivation reporter systems. , 2009, Human molecular genetics.

[51]  Colleen D. McCabe,et al.  Molecular characterization of HOXA13 polyalanine expansion proteins in hand–foot–genital syndrome , 2007, American journal of medical genetics. Part A.

[52]  A. Wills,et al.  Oculopharyngeal muscular dystrophy: a point mutation which mimics the effect of the PABPN1 gene triplet repeat expansion mutation , 2005, Journal of Medical Genetics.

[53]  S. Bale,et al.  The full spectrum of holoprosencephaly‐associated mutations within the ZIC2 gene in humans predicts loss‐of‐function as the predominant disease mechanism , 2009, Human mutation.

[54]  J. Opitz,et al.  HOXD13 polyalanine tract expansion in classical synpolydactyly type Vordingborg. , 2002, American journal of medical genetics.

[55]  M. Mangelsdorf,et al.  Aristaless-related homeobox gene, the gene responsible for West syndrome and related disorders, is a Groucho/transducin-like enhancer of split dependent transcriptional repressor , 2007, Neuroscience.

[56]  M. Hentze,et al.  3′ end mRNA processing: molecular mechanisms and implications for health and disease , 2008, The EMBO journal.

[57]  J. Taylor,et al.  Repeat expansion disease: progress and puzzles in disease pathogenesis , 2010, Nature Reviews Genetics.

[58]  L. Donahue,et al.  A new spontaneous mouse mutation of Hoxd13 with a polyalanine expansion and phenotype similar to human synpolydactyly. , 1998, Human molecular genetics.

[59]  M. Cunningham,et al.  Cleidocranial dysplasia with severe parietal bone dysplasia: C-terminal RUNX2 mutations. , 2006, Birth defects research. Part A, Clinical and molecular teratology.

[60]  C. McMurray.  Mechanisms of trinucleotide repeat instability during human development , 2010, Nature Reviews Genetics.

[61]  W. Dobyns,et al.  Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans , 2002, Nature Genetics.

[62]  J. Gécz,et al.  Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene. , 2007, Genomics.

[63]  A. Munnich,et al.  Polyalanine expansions might not result from unequal crossing‐over , 2007, Human Mutation.

[64]  P. Lockhart,et al.  Polyalanine expansion mutations in the X-linked hypopituitarism gene SOX3 result in aggresome formation and impaired transactivation. , 2007, Frontiers in bioscience : a journal and virtual library.

[65]  S. T. Warren,et al.  Polyalanine Expansion in Synpolydactyly Might Result from Unequal Crossing-Over of HOXD13 , 1997, Science.

[66]  N. Nukina,et al.  The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies , 2009, Journal of neurochemistry.

[67]  B. Brais,et al.  Polymorphism, shared functions and convergent evolution of genes with sequences coding for polyalanine domains. , 2003, Human molecular genetics.

[68]  E. Zackai,et al.  Mutations of ARX are associated with striking pleiotropy and consistent genotype–phenotype correlation , 2004, Human mutation.

[69]  J. Gécz,et al.  Clinical study of two brothers with a novel 33 bp duplication in the ARX gene , 2009, American journal of medical genetics. Part A.

[70]  B. Maher,et al.  Idiopathic congenital central hypoventilation syndrome: Analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b , 2003, American journal of medical genetics. Part A.

[71]  N. Bonini,et al.  Roles of trinucleotide-repeat RNA in neurological disease and degeneration , 2010, Trends in Neurosciences.

[72]  I. Scheffer,et al.  Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy , 2002, Nature Genetics.

[73]  M. Fardeau,et al.  Nuclear inclusion in oculopharyngeal dystrophy , 2004, Acta Neuropathologica.

[74]  K. Devriendt,et al.  UvA-DARE ( Digital Academic Repository ) FOXL 2 and BPES : Mutational hotspots , phenotypic variability , and revision of the genotype-phenotype correlation , 2017 .

[75]  R. Arkell,et al.  In vitro analysis of partial loss-of-function ZIC2 mutations in holoprosencephaly: alanine tract expansion modulates DNA binding and transactivation. , 2005, Human molecular genetics.

[76]  Mark F. Bear,et al.  Correction of Fragile X Syndrome in Mice , 2007, Neuron.

[77]  J. Lupski,et al.  A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders , 2007, Cell.

[78]  J. Gécz,et al.  ARX spectrum disorders: making inroads into the molecular pathology , 2010, Human mutation.

[79]  B. Brais,et al.  PABPN1 polyalanine tract deletion and long expansions modify its aggregation pattern and expression. , 2008, Experimental cell research.

[80]  Denis Duboule,et al.  Hox genes in digit development and evolution , 1999, Cell and Tissue Research.

[81]  J. Fryns,et al.  ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. , 2002, Human molecular genetics.

[82]  M. Carmo-Fonseca,et al.  Hsp70 Chaperones and Type I PRMTs Are Sequestered at Intranuclear Inclusions Caused by Polyalanine Expansions in PABPN1 , 2009, PloS one.

[83]  R. Lovell-Badge,et al.  Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. , 2005, American journal of human genetics.

[84]  D. Robinson,et al.  Oculopharyngeal muscular dystrophy (OPMD): analysis of the PABPN1 gene expansion sequence in 86 patients reveals 13 different expansion types and further evidence for unequal recombination as the mutational mechanism , 2005, Human Genetics.