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(ZNF81) Mutations Associated with X-Linked Mental Retardation

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(ZNF81) Mutations Associated with X-Linked Mental Retardation 394 LETTER TO JMG J Med Genet: first published as 10.1136/jmg.2003.016972 on 30 April 2004. Downloaded from Zinc finger 81 (ZNF81) mutations associated with X-linked mental retardation T Kleefstra, H G Yntema, A R Oudakker, M J G Banning, V M Kalscheuer, J Chelly, C Moraine, H-H Ropers, J-P Fryns, I M Janssen, E A Sistermans, W N Nillesen, L B A de Vries, B C J Hamel, H van Bokhoven ............................................................................................................................... J Med Genet 2004;41:394–399. doi: 10.1136/jmg.2003.016972 -linked mental retardation (XLMR) has a prevalence of Key points 2.6 cases per 1000 population, accounting for over 10% Xof all cases of mental retardation. Clinically, XLMR exists in syndromic (MRXS) and non-syndromic (MRX) N We have cloned the breakpoints of a de novo forms, that is without other distinguishing features. translocation t(X;9)(p11.23;q34.3) in a mentally Non-syndromic X-linked mental retardation (MRX) is a retarded female. The translocation disrupts the gene highly heterogeneous group of conditions in which mental ZNF81 on the X chromosome. retardation (MR) is the only consistent clinical feature in N ZNF81 is highly homologous to ZNF41, another zinc patients. This in contrast to syndromic forms of X-linked finger gene associated with non-specific X-linked mental retardation (MRXS), where MR is associated with mental retardation. recognisable clinical signs such as congenital malformations, N Mutation analysis in more than 300 families and neurological features, or metabolic disturbances. Identifying patients with non-specific X-linked mental retardation novel genes that are responsible for MRX is difficult due to revealed a sequence change p.S179N in MRX45, fully the heterogeneity of this disorder. At present 30 genes have segregating with the phenotype. been identified as playing a role in MRXS. However in MRX, only 15 genes are known to be involved accounting for less N It is likely that ZNF81 represents a novel MRX gene than one-fifth of all MRX.1–6 The recent observations that which is causally involved in a minority of patients with RSK2, MECP2, and ARX play a role in both syndromic and non-specific X-linked mental retardation. non-syndromic forms of XLMR,7–10 suggest that a molecular basis to strictly separate these two forms is not always present. In addition, careful clinical re-examination of a birth length of 49 cm (25th centile). Pregnancy and delivery patients with an OPHN1 gene mutation has revealed were uneventful. She was the second daughter of healthy, distinctive phenotypic hallmarks, such as cerebellar hypo- non-consanguineous parents. In the neonatal period hypo- plasia, in patients who were previously classified as non- tonia and feeding problems were present. The anterior http://jmg.bmj.com/ 11 12 syndromic. fontanel was enlarged and closed at the age of 2 years. The frequency of causative mutations in any of the 15 MRX Psychomotor development was delayed and she walked at genes known today appears to be very low, so in the majority the age of 2 years and 6 months, with hardly any speech of patients with MRX the genetic cause is still not known. It development. She had a mild-moderate conductive hearing has been suggested that up to 100 different genes might be loss on both sides. At the age of 2 years, an atrial septum involved in MRX.1–4 Seven of the 15 genes have been cloned defect type II with a pulmonary stenosis was diagnosed on the basis of their disruption by chromosomal rearrange- without haemodynamic consequence. ments in mentally retarded patients. Recently, it has been on October 1, 2021 by guest. Protected copyright. At the age of 4 years, she had epileptic convulsions with predicted that approximately 30% of all mutations underlying EEG abnormalities, but thereafter no more convulsions MRX are located in the Xp11.2–Xp11.3 interval.1 Only two MRX genes have so far been identified in this region, ZNF415 occurred and EEG patterns returned to normal. She had and PQBP1.6 In this study, we have characterised the severe behavioural problems involving autistic features, breakpoint of a de novo translocation t(X;9)(p11.23;q34.3) aggressiveness, and auto-mutilation. The menarche started in a female patient with severe mental retardation. Since the at 10 years of age. At the age of 11 years, she was a non- breakpoint on the X chromosome is within the hotspot cooperative, mildly obese girl with apparently normal height interval of MRX genes, it was an excellent starting point for a and head circumference, brachycephalic skull and several positional cloning approach to identify a novel candidate facial dysmorphisms: synophrys, upward slanting of the gene responsible for MRX. Fine-mapping of the X-chromo- palpebral fissures, hypertelorism, a broad nasal bridge, somal breakpoint with fluorescence in situ hybridisation protrusion of the tongue, eversion of the lower lip, and small (FISH) analysis and sequencing led to the identification of a ears. gene, ZNF81, that was disrupted by the breakpoint. Subsequent mutation analysis in a cohort of MRX families XLMR families and controls revealed a missense mutation in a family that maps to DNA from approximately 300 families collected by the Xp11.23, supporting the notion that ZNF81 is a novel MRX European XLMR Consortium, including 24 families with gene. linkage to the Xp11.23 region (LOD score .2), were available for mutation screening (www.euromrx.com). METHODS Propositus The patient was a Caucasian girl born after 37 weeks Abbreviations: FISH, fluorescence in situ hybridisation; MR, mental gestation, with a birth weight of 3100 g (25th centile) and retardation; XLMR, X-linked mental retardation; ZNF81,zinc finger 81 www.jmedgenet.com Letter to JMG 395 DNA from 241 Caucasian control males and 105 control Mutation screening in XLMR probands females was available to verify the incidence of nucleotide The entire coding region of the ZNF81 gene was sequenced in J Med Genet: first published as 10.1136/jmg.2003.016972 on 30 April 2004. Downloaded from changes. In addition, 217 MR males negative for FMR1 536 MR patients, that is 319 from the European XLMR trinucleotide expansions were also analysed for mutations in Consortium and 217 MR males negative for FMR1 mutations, the ZNF81 gene. using genomic DNA as a template. Primers were designed to amplify the non-coding exons 1 and 2 and coding exons 3–6 Fluorescence in situ hybridisation (FISH) of the gene. Exon 6 was amplified in three overlapping BACs on chromosome Xp11.2 and 9q34.3 were selected from fragments (6a,b,c). Primers and PCR conditions are shown in the UCSC Genome browser (http://genome.ucsc.edu) and table 1. The PCR samples were directly sequenced, after obtained from the Max Planck Institute, Berlin. DNA from purification with a Qiagen PCR purification kit, on an BACs was labelled with digoxigenin-dUTP by nick translation Applied Biosystems 3730 automated sequencer using the (Invitrogen) or by random priming with biotine-dNTP by same primers as in the PCR. Klenow polymerase (Roche). The hybridisation signals were made visible by antibody-FITC or by avidine-Cy3 labelled RESULTS antibodies on a Leica DMRA fluorescence microscope. Mapping of chromosome Xp11.23 and chromosome 9q34.3 breakpoints using FISH Southern blotting Successive fluorescent in situ hybridisation with nine over- DNA samples of cell lines of the patient, one control female, lapping BAC clones showed that RP11-1145B22 gave signals X chromosome hamster somatic hybrid, and hamster, on the derivative chromosome X as well as on the derivative were digested with five different restriction endonucleases chromosome 9 (fig 2), which indicated that the breakpoint (BamHI, BglII, EcoRI, HindIII, SmaI), electrophoresed on region on the X chromosome was located within this clone. (0.6%) agarose gels and transferred in 1.5 M NaCl/0.5 N The overlapping neighbouring clones, RP3-393P12 at the NaOH to nylon membranes (Genescreen) according to distal side and RP11-1154B20 at the proximal side, gave standard protocols. signals on only one of the translocation chromosomes, the cDNA fragments or genomic DNA templates were used to derivative-9 and derivative-X, respectively (data not shown). generate probes by extension of random hexamer primers It thus seemed that the X-chromosomal breakpoint is located with Klenow polymerase in the presence of [32P]dCTP. in a 40 kb fragment that is unique to RP11-1145B22. Probes were hybridised to the Southern blots in 0.125 M PO4, 0.25 M NaCl, 1 mM EDTA, 7% (w/v) SDS, 10% (w/v) In silico analysis PEG 6000 overnight at 65˚C. In silico analysis using the UCSC genome browser, http:// Blots were washed in 40 mM NaPO4/0.5% SDS at 65˚C and genome.ucsc.edu/cgi-bin/hgGateway (accessed in March 2004), exposed to radiographic film. revealed several spliced ESTs but no known genes, mapping to the breakpoint region. The spliced ESTs did Vectorette PCR not have a long open reading frame (ORF). However, A vectorette-PCR cloning procedure was used essentially as several of these ESTs showed homology to KRAB-domain described by the manufacturer at www.genosys.com. Briefly, coding sequences, which are commonly found in zinc BamH1 digested DNA from the patient and a control was finger proteins. Further BLAST searches with sequences ligated to a phosphorylated BamH1-vectorette top strand from BAC RP11-1145B22 resulted in the identification of primer (VTSP-BamHI; 59-GATCCAAGGAGAGGACGCTGG sequences encoding zinc finger motifs that had the same http://jmg.bmj.com/ TCTGTCGAAGGTAAGGAACGAACGAGAGAAGGGAGAG-39) orientation as the KRAB-domain sequences. It appeared and a phosphorylated vectorette bottom strand primer that merging of six of the predicted exons of the region (VBSP; 59-CTCTCCCTTCTCGAATCGTAACCGTTCGTACGAG had the capacity to form a transcript with an ORF of AATCGCTGTCCCTCTCCTTG-39) o/n at 16˚C.
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