Novel Truncating Mutations in the Polyglutamine Tract Binding Protein 1 Gene (PQBP1) Cause Renpenning Syndrome and X-Linked Mental Retardation in Another Family with Microcephaly

Lenski, C; Abidi, Fatima; Meindl, Alfons; Gibson, Alice; Platzer, Matthias; Kooy, R. Frank; Lubs, Herbert A.; Stevenson, Roger E.; Ramser, Juliane; Schwartz, Charles E.

doi:10.1086/383205

Cited by 68 publications

(52 citation statements)

References 17 publications

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“…Because the PQBP1 gene is responsible for human MR (Kalscheuer et al, 2003;Kleefstra et al, 2004;Lenski et al, 2004), we tested learning and memory retention in the mutant flies. To evaluate their memory, we used olfactory conditioning (Tully and Quinn, 1985) and found that the homozygous dPQBP1 mutant showed a statistically significant decrease in PI within 3 min after single training (Fig.…”

Section: Dpqbp1 Reduction Impairs Learning Acquisitionmentioning

confidence: 99%

“…An increasing number of clinical reports have indicated that PQBP1-linked MR syndromes have a high frequency (Stevenson et al, 2005) with recent data from the European Consortium of X-Linked MR suggesting that it might be almost equivalent to Rett syndrome (Poirier et al, 2006). Most PQBP-1 mutations induce truncation of C-terminal domain (CTD) by frameshift (Kalscheuer et al, 2003;Kleefstra et al, 2004;Lenski et al, 2004) or reduction of PQBP1 mRNA by non-sense decay (Kalscheuer et al, 2003). Conversely, in our analyses of transgenic mice expressing truncated PQBP1 cDNA, we detected a faint band of PQBP1 by Western blot analysis, although almost no PQBP1 was evident in the brain (our unpublished observation).…”

Section: Introductionmentioning

confidence: 99%

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DrosophilaPQBP1 Regulates Learning Acquisition at Projection Neurons in Aversive Olfactory Conditioning

Tamura

Horiuchi²,

Chen³

et al. 2010

J. Neurosci.

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Polyglutamine tract-binding protein-1 (PQBP1) is involved in the transcription-splicing coupling, and its mutations cause a group of human mental retardation syndromes. We generated a fly model in which the Drosophila homolog of PQBP1 (dPQBP1) is repressed by insertion of piggyBac. In classical odor conditioning, learning acquisition was significantly impaired in homozygous piggyBac-inserted flies, whereas the following memory retention was completely normal. Mushroom bodies (MBs) and antennal lobes were morphologically normal in dPQBP1-mutant flies. Projection neurons (PNs) were not reduced in number and their fiber connections were not changed, whereas gene expressions including NMDA receptor subunit 1 (NR1) were decreased in PNs. Targeted double-stranded RNAmediated silencing of dPQBP1 in PNs, but not in MBs, similarly disrupted learning acquisition. NR1 overexpression in PNs rescued the learning disturbance of dPQBP1 mutants. HDAC (histone deacetylase) inhibitors, SAHA (suberoylanilide hydroxamic acid) and PBA (phenylbutyrate), that upregulated NR1 partially rescued the learning disturbance. Collectively, these findings identify dPQBP1 as a novel gene regulating learning acquisition at PNs.

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Section: Dpqbp1 Reduction Impairs Learning Acquisitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DrosophilaPQBP1 Regulates Learning Acquisition at Projection Neurons in Aversive Olfactory Conditioning

Tamura

Horiuchi²,

Chen³

et al. 2010

J. Neurosci.

View full text Add to dashboard Cite

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“…Polyglutamine binding protein-1 (PQBP1) is a 38 kDa nuclear protein abundantly expressed in the adult mammalian central nervous system (Komuro et al, 1999a;Waragai et al, 1999), and mutations in the human PQBP1 gene cause X-linked intellectual disability (XLID) diseases that include Renpenning, SutherlandHaan, Hamel cerebropalatocardiac, Golabi-Ito-Hall and Porteous syndromes (Kalscheuer et al, 2003;Lenski et al, 2004;Stevenson et al, 2005;Cossee et al, 2006;Lubs et al, 2006;Martinez-Garay et al, 2007). These are collectively referred to as Renpenning syndrome, and affected patients display unifying clinical features, including intellectual disability, microcephaly and short stature.…”

Section: Introductionmentioning

confidence: 99%

The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling

Iwasaki

Thomsen

2014

Development

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Alternative splicing of pre-mRNAs is an important means of regulating developmental processes, yet the molecular mechanisms governing alternative splicing in embryonic contexts are just beginning to emerge. Polyglutamine-binding protein 1 (PQBP1) is an RNAsplicing factor that, when mutated, in humans causes Renpenning syndrome, an X-linked intellectual disability disease characterized by severe cognitive impairment, but also by physical defects that suggest PQBP1 has broader functions in embryonic development. Here, we reveal essential roles for PQBP1 and a binding partner, WBP11, in early development of Xenopus embryos. Both genes are expressed in the nascent mesoderm and neurectoderm, and morpholino knockdown of either causes defects in differentiation and morphogenesis of the mesoderm and neural plate. At the molecular level, knockdown of PQBP1 in Xenopus animal cap explants inhibits target gene induction by FGF but not by BMP, Nodal or Wnt ligands, and knockdown of either PQBP1 or WBP11 in embryos inhibits expression of fgf4 and FGF4-responsive cdx4 genes. Furthermore, PQBP1 knockdown changes the alternative splicing of FGF receptor-2 (FGFR2) transcripts, altering the incorporation of cassette exons that generate receptor variants (FGFR2 IIIb or IIIc) with different ligand specificities. Our findings may inform studies into the mechanisms underlying Renpenning syndrome.

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“…Similar to ARX, this gene presents a mutation hot spot (a dinucleotide repeat that is subject to insertions/deletions) and was found mutated in both nonsyndromic MR families, but also in MR associated with microcephaly and/or short stature, including the classic Renpenning syndrome family. 38,39 More generally, new genetic epidemiology studies on mental retardation should be performed, as improved control of perinatal causes of brain damage may have affected the proportion of genetic versus nongenetic cases, and taking into account the recent progress in diagnosis of specific conditions (fragile X, microdeletion syndromes or telomere rearrangements). This would allow a re-evaluation of recurrence risks in function of the sex of proband Hypothesis:% XLMR in MR males/% of dup24 in XLMR.…”

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confidence: 99%

Monogenic X-linked mental retardation: Is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations

2004

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Mental retardation affects 30 to 50% more males than females, and X-linked mental retardation (XLMR) is thought to account for the major part of this sex bias. Nonsyndromic XLMR is very heterogeneous, with more than 15 genes identified to date, each of them accounting for a very small proportion of nonsyndromic families. The Aristaless X (ARX) gene is an exception since it was found mutated in 11 of 136 such families, with a highly recurrent mutation (dup24) leading to an expansion of a polyalanine tract in the protein. The rather high frequency of dup24 reported in families with clear X-linked MR (6.6%) contrasts with the very low prevalence of this mutation observed in sporadic male MR (0.13%). We conclude that monogenic XLMR has much lower prevalence in male MR (o10%) than the 23% that would be required to account for a 30% male excess of mental retardation.

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Novel Truncating Mutations in the Polyglutamine Tract Binding Protein 1 Gene (PQBP1) Cause Renpenning Syndrome and X-Linked Mental Retardation in Another Family with Microcephaly

Cited by 68 publications

References 17 publications

DrosophilaPQBP1 Regulates Learning Acquisition at Projection Neurons in Aversive Olfactory Conditioning

DrosophilaPQBP1 Regulates Learning Acquisition at Projection Neurons in Aversive Olfactory Conditioning

The splicing factor PQBP1 regulates mesodermal and neural development through FGF signaling

Monogenic X-linked mental retardation: Is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations

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