The Contribution of CLIP2 Haploinsufficiency to the Clinical Manifestations of the Williams-Beuren Syndrome
2012; Elsevier BV; Volume: 90; Issue: 6 Linguagem: Inglês
10.1016/j.ajhg.2012.04.020
ISSN1537-6605
AutoresGeert Vandeweyer, Nathalie Van der Aa, Edwin Reyniers, R. Frank Kooy,
Tópico(s)Nuclear Receptors and Signaling
ResumoWilliams-Beuren syndrome is a rare contiguous gene syndrome, characterized by intellectual disability, facial dysmorphisms, connective-tissue abnormalities, cardiac defects, structural brain abnormalities, and transient infantile hypercalcemia. Genes lying telomeric to RFC2, including CLIP2, GTF2I and GTF2IRD1, are currently thought to be the most likely major contributors to the typical Williams syndrome cognitive profile, characterized by a better-than-expected auditory rote-memory ability, a relative sparing of language capabilities, and a severe visual-spatial constructive impairment. Atypical deletions in the region have helped to establish genotype-phenotype correlations. So far, however, hardly any deletions affecting only a single gene in the disease region have been described. We present here two healthy siblings with a pure, hemizygous deletion of CLIP2. A putative role in the cognitive and behavioral abnormalities seen in Williams-Beuren patients has been suggested for this gene on the basis of observations in a knock-out mouse model. The presented siblings did not show any of the clinical features associated with the syndrome. Cognitive testing showed an average IQ for both and no indication of the Williams syndrome cognitive profile. This shows that CLIP2 haploinsufficiency by itself does not lead to the physical or cognitive characteristics of the Williams-Beuren syndrome, nor does it lead to the Williams syndrome cognitive profile. Although contribution of CLIP2 to the phenotype cannot be excluded when it is deleted in combination with other genes, our results support the hypothesis that GTF2IRD1 and GTF2I are the main genes causing the cognitive defects associated with Williams-Beuren syndrome. Williams-Beuren syndrome is a rare contiguous gene syndrome, characterized by intellectual disability, facial dysmorphisms, connective-tissue abnormalities, cardiac defects, structural brain abnormalities, and transient infantile hypercalcemia. Genes lying telomeric to RFC2, including CLIP2, GTF2I and GTF2IRD1, are currently thought to be the most likely major contributors to the typical Williams syndrome cognitive profile, characterized by a better-than-expected auditory rote-memory ability, a relative sparing of language capabilities, and a severe visual-spatial constructive impairment. Atypical deletions in the region have helped to establish genotype-phenotype correlations. So far, however, hardly any deletions affecting only a single gene in the disease region have been described. We present here two healthy siblings with a pure, hemizygous deletion of CLIP2. A putative role in the cognitive and behavioral abnormalities seen in Williams-Beuren patients has been suggested for this gene on the basis of observations in a knock-out mouse model. The presented siblings did not show any of the clinical features associated with the syndrome. Cognitive testing showed an average IQ for both and no indication of the Williams syndrome cognitive profile. This shows that CLIP2 haploinsufficiency by itself does not lead to the physical or cognitive characteristics of the Williams-Beuren syndrome, nor does it lead to the Williams syndrome cognitive profile. Although contribution of CLIP2 to the phenotype cannot be excluded when it is deleted in combination with other genes, our results support the hypothesis that GTF2IRD1 and GTF2I are the main genes causing the cognitive defects associated with Williams-Beuren syndrome. Williams-Beuren syndrome (WBS [MIM 194050]) is a rare neurodevelopmental disorder with an estimated frequency of 1/7,500 to 1/15,000. The WBS phenotype includes recognizable facial dysmorphisms, connective tissue abnormalities, cardiac defects (SVAS/PPS), structural brain abnormalities, transient infantile hypercalcemia, and a specific cognitive profile.1Tassabehji M. Williams-Beuren syndrome: A challenge for genotype-phenotype correlations.Hum. Mol. Genet. 2003; 12: R229-R237Crossref PubMed Scopus (150) Google Scholar, 2Jackowski A.P. Rando K. Maria de Araújo C. Del Cole C.G. Silva I. Tavares de Lacerda A.L. Brain abnormalities in Williams syndrome: a review of structural and functional magnetic resonance imaging findings.Eur. J. Paediatr. Neurol. 2009; 13: 305-316Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 3Pober B.R. Williams-Beuren syndrome.N. Engl. J. 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Boyd C.D. Thibodeau S.N. A 30 kb deletion within the elastin gene results in familial supravalvular aortic stenosis.Hum. Mol. Genet. 1995; 4: 1677-1679Crossref PubMed Scopus (83) Google Scholar We present a pure, hemizygous CLIP2 deletion in two unaffected siblings. The intragenic deletion was initially identified as a supplementary finding in a patient referred to our department on indication of global developmental delay and microcephaly. As a toddler, he was diagnosed with autism on the basis of repetitive behavior, poor interaction skills, and hand flapping. Psycho-diagnostic evaluation at the age of 15 years showed a total IQ of 69 (WISC-R). In late adolescence he developed visual as well as auditory hallucinations and was diagnosed with schizophrenia. Dysmorphic features, apart from microcephaly, included long palpebral fissures, a high nasal bridge, and a prominent inverted lower lip. We detected a 580 kb microduplication at 16p11.2 (MIM 611913) by using an Illumina HumanCNV370-Quad BeadChip. The clinical presentation of this patient fits well within the described phenotype of carriers of a 16p11.2 microduplication. The phenotype of the patient is thus fully explained by the de novo 16p11.2 microduplication.30Shinawi M. Liu P. Kang S.H. Shen J. Belmont J.W. Scott D.A. Probst F.J. Craigen W.J. Graham B.H. Pursley A. et al.Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size.J. Med. Genet. 2010; 47: 332-341Crossref PubMed Scopus (367) Google Scholar, 31Jacquemont S. Reymond A. Zufferey F. Harewood L. Walters R.G. Kutalik Z. Martinet D. Shen Y. Valsesia A. Beckmann N.D. et al.Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus.Nature. 2011; 478: 97-102Crossref PubMed Scopus (336) Google Scholar With the approval of the institutional ethics committee, the patients' DNA was included in a follow-up research cohort. Refined data analysis with CNV-WebStore identified an additional deletion, ranging from position 73,760,704 to 73,810,096, of five consecutive probes in CLIP2 on chromosome 7q11.23.32Vandeweyer G. Reyniers E. Wuyts W. Rooms L. Kooy R.F. CNV-WebStore: Online CNV analysis, storage and interpretation.BMC Bioinformatics. 2011; 12: 4Crossref PubMed Scopus (41) Google Scholar The deletion was confirmed by reanalysis on an Illumina HumanCyto12-v1.0 BeadChip. On the basis of the higher coverage of 19 consecutive probes in this disease-associated region, the deletion was predicted to range from position 73,734,542 to 73,815,967. MLPA analysis showed that the CLIP2 deletion was also present in the unaffected mother and her brother, referred to as “healthy siblings,” whereas the duplication of 16p11.2 in the autistic patient appeared de novo.33Rooms L. Vandeweyer G. Reyniers E. van Mol K. de Canck I. Van der Aa N. Rossau R. Kooy R.F. Array-based MLPA to detect recurrent copy number variations in patients with idiopathic mental retardation.Am. J. Med. Genet. A. 2011; 155A: 343-348Crossref PubMed Scopus (12) Google Scholar PCR primers spanning the deletion were designed, allowing characterization of the breakpoints at the nucleotide level. The deleted region spanned 83 kb, ranging from position 73,740,492 to 73,823,520 (NCBI GRCh37). The proximal breakpoint is located in intron 2 of CLIP2, and the distal breakpoint maps in the intergenic region between CLIP2 and GTF2IRD1 (Figure 1). Both breakpoints were located in AluSz repeats as identified by RepeatMasker (Figure 2).34Smit, A.F.A., Hubley, R., Green, P. (1996) RepeatMasker Open-3.0.Google Scholar Locally aligning these elements by using LALIGN showed more than 82% similarity between the flanking repeats and 26 base pairs of perfect identity at the breakpoints, indicating Alu-mediated, unequal homologous recombination as the causative mechanism for the rearrangement.35Pearson W.R. Wood T. Zhang Z. Miller W. Comparison of DNA sequences with protein sequences.Genomics. 1997; 46: 24-36Crossref PubMed Scopus (481) Google Scholar, 36Batzer M.A. Deininger P.L. Alu repeats and human genomic diversity.Nat. Rev. Genet. 2002; 3: 370-379Crossref PubMed Scopus (1048) Google ScholarFigure 2AluSz Alignment wth the LALIGN ProgramShow full captionBreakpoint position is indicated by a red rectangle around the flanking nucleotides. Proximal AluSz coordinates: chr7:73,740,287–73,740,582 with the breakpoint at position 73,740,492. Distal AluSx coordinates: chr7:73,823,314–73,823,618 with the breakpoint at position 73,823,520.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Breakpoint position is indicated by a red rectangle around the flanking nucleotides. Proximal AluSz coordinates: chr7:73,740,287–73,740,582 with the breakpoint at position 73,740,492. Distal AluSx coordinates: chr7:73,823,314–73,823,618 with the breakpoint at position 73,823,520. Expression of the CLIP2, CLIP1, GTF2IRD1, GTF2I, LAT2, RFC2, STX1A, and WBSCR22 genes was examined by qPCR on lymphoblastoid cell lines with GAPDH, YWAZ, and HPRT as reference genes (Figure 3). A set of 15 cognitively tested individuals of normal intelligence was used as a control. Because no lymphoblastoid material was available from the male sibling, two replicate cDNA syntheses from two independent cell lines of the female sibling were used as test samples. A significant reduction of CLIP2 expression to about 40% residual expression was detected (p < 0.001). No evidence of a compensation effect by CLIP1 overexpression was found. No significant alterations in the expression of GTF2I, LAT2, RFC2, STX1A, or WBSCR22 was detected, but the expression of GTF2IRD1, located 48 kb 3′ of CLIP2, was significantly increased (p < 0.001) in comparison to the normal controls. These results are in line with studies in full-deletion WBS patients, demonstrating that the expression of most candidate genes, including CLIP2, is reduced to 50% of the level observed in controls when this expression is analyzed in lymphoblast cell lines.37Gao M.C. Bellugi U. Dai L. Mills D.L. Sobel E.M. Lange K. Korenberg J.R. Intelligence in Williams Syndrome is related to STX1A, which encodes a component of the presynaptic SNARE complex.PLoS ONE. 2010; 5: e10292Crossref PubMed Scopus (36) Google Scholar, 38Henrichsen C.N. Csárdi G. Zabot M.T. Fusco C. Bergmann S. Merla G. Reymond A. Using transcription modules to identify expression clusters perturbed in Williams-Beuren syndrome.PLoS Comput. Biol. 2011; 7: e1001054Crossref PubMed Scopus (24) Google Scholar, 39Merla G. Howald C. Henrichsen C.N. Lyle R. Wyss C. Zabot M.T. Antonarakis S.E. Reymond A. Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes.Am. J. Hum. Genet. 2006; 79: 332-341Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar In contrast, no reduction in GTF2IRD1 expression is observed in this cell type for typical WBS patients, presumably as a consequence of a negative autoregulation mechanism.18Antonell A. Del Campo M. Magano L.F. Kaufmann L. de la Iglesia J.M. Gallastegui F. Flores R. Schweigmann U. Fauth C. Kotzot D. Pérez-Jurado L.A. Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile.J. Med. Genet. 2010; 47: 312-320Crossref PubMed Scopus (94) Google Scholar, 19Edelmann L. Prosnitz A. Pardo S. Bhatt J. Cohen N. Lauriat T. Ouchanov L. González P.J. Manghi E.R. Bondy P. et al.An atypical deletion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism.J. Med. Genet. 2007; 44: 136-143Crossref PubMed Scopus (85) Google Scholar, 40Palmer S.J. Santucci N. Widagdo J. Bontempo S.J. Taylor K.M. Tay E.S. Hook J. Lemckert F. Gunning P.W. Hardeman E.C. Negative autoregulation of GTF2IRD1 in Williams-Beuren syndrome via a novel DNA binding mechanism.J. Biol. Chem. 2010; 285: 4715-4724Crossref PubMed Scopus (20) Google Scholar In fibroblast cell lines, however, the expression of GTF2IRD1 is reduced, indicating tissue-specific regulation.39Merla G. Howald C. Henrichsen C.N. Lyle R. Wyss C. Zabot M.T. Antonarakis S.E. Reymond A. Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes.Am. J. Hum. Genet. 2006; 79: 332-341Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Due to this tissue-dependent regulation, the relevance of the observed overexpression of GTF2IRD1 in blood cells of the female sibling is unclear, and expression might be differently affected in the central nervous system. Both siblings with the pure CLIP2 deletion are healthy adults of European descent in their fifties with an unremarkable medical, developmental, and academic history. The woman has worked as a solicitor's secretary for the last 25 years, and her brother is a librarian. Both of them are married and have children. Contrary to adults with the WBS, they have a normal body habitus and an average proportional stature.41Pober B.R. Morris C.A. Diagnosis and management of medical problems in adults with Williams-Beuren syndrome.Am. J. Med. Genet. C. Semin. Med. Genet. 2007; 145C: 280-290Crossref PubMed Scopus (64) Google Scholar There is no hearing impairment, there are no signs of cardiovascular disease or hypertension, and there is no history of gastrointestinal problems or diabetes. On physical examination, there is no scoliosis and no stiffness or hypermobility in the joints. There is no premature greying of the hair or sagging of the cheeks, as seen in adults with WBS. The typical dysmorphic features of WBS in adults are a wide mouth and prominent lips together with prominence of the supra orbital ridges and a narrow nasal root, and these features were not present in the siblings. Neurological examination in the female sibling showed slight divergent strabismus of the right eye and a weakness in focalization, leading to a suspicion of amblyopia. This was not confirmed by an ophthalmologist. Examination of ocular motility was otherwise normal. Cranial nerve evaluation showed no abnormalities. Peripheral motor and sensibility evaluation as well as reflexes were all normal. Coordination, gait, and equilibrium were normal. She has no history of psychiatric signs or symptoms. Psychiatric evaluation did not reveal any signs of comorbid behavioral or the mental-health problems, such as generalized anxiety, attention-deficit hyperactivity disorder, depression, and phobias and obsessions, that are seen in WBS patients.41Pober B.R. Morris C.A. Diagnosis and management of medical problems in adults with Williams-Beuren syndrome.Am. J. Med. Genet. C. Semin. Med. Genet. 2007; 145C: 280-290Crossref PubMed Scopus (64) Google Scholar, 42Elison S. Stinton C. Howlin P. Health and social outcomes in adults with Williams syndrome: Findings from cross-sectional and longitudinal cohorts.Res. Dev. Disabil. 2010; 31: 587-599Crossref PubMed Scopus (47) Google Scholar The brother has no obvious neurological or psychiatric abnormalities, but thorough examination by a neurologist was not performed. Both siblings were subjected to formal cognitive testing with Wechsler Adult Intelligence Scales (WAIS-III, The Psychological Corporation, 1997). Verbal IQ was scored by seven tests: vocabulary, similarities, calculating, series of numbers, information, understanding, and repeating of numbers and letters. Five tests were used for performance IQ testing: symbol substitution, picture arrangement, matrix reasoning, object assembly, and block design. The majority of adult WBS patients score in the mild range of intellectual disability (55 to 69 IQ points) on standardized intelligence tests and have a slightly higher VIQ than PIQ score, although this difference is not significant in most cases.7Howlin P. Elison S. Udwin O. Stinton C. Cognitive, linguistic and adaptive functioning in Williams Syndrome: Trajectories from early to middle adulthood.J. Appl. Res. Intellect. Disabil. 2010; 23: 322-336Crossref Scopus (24) Google Scholar It can be appreciated from Figure 4 and Table 1 that the siblings' obtained IQ scores closely resemble a normal cognitive profile. Both siblings performed on an average to above-average level on the different indices. The brother's verbal IQ was 5 points higher than performance IQ, and the sister's verbal IQ was 6 points lower. Thus, the siblings showed small but non-significant and reciprocal differences between verbal and performance IQ. The four secondary indices of the WAIS-III (verbal comprehension, working memory, perceptual organization, and processing speed) were also scored so that maximum information on the cognitive strengths and weaknesses of the patients would be available. No evidence for a relative verbal strength was present at this level either. The brother did not show any significant differences between the individual index scores, whereas the sister showed significant relative strengths in working memory and processing speed, contributing to verbal and performance IQ scores, respectively.Table 1WAIS-III Results of the Cognitive Profiling in Both Deletion CarriersFemale CarrierMale CarrierGlobal IQ107105Performal IQ111103Verbal IQ105107Verbal comprehension index (VCI)103105Perceptual organisationindex (POI)99107Working memory index (WMI)122114Processing speed index (PSI)123103Significant differencesWMI and PSI versus VCI and PRInoneFormal cognitive testing was performed by a trained psychologist. The significance threshold was taken from the WAIS III NL Technische Handleiding (Pearson, Amsterdam, The Netherlands). Significant deviations between secondary indices and verbal or performance IQ are defined as deviations seen in less than 5% from the standardized sample used for calibration of the test. Open table in a new tab Formal cognitive testing was performed by a trained psychologist. The significance threshold was taken from the WAIS III NL Technische Handleiding (Pearson, Amsterdam, The Netherlands). Significant deviations between secondary indices and verbal or performance IQ are defined as deviations seen in less t
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