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AP1S2 Is Mutated in X-Linked Dandy&Ndash;Walker Malformation with Intellectual Disability, Basal Ganglia Disease and Seizure

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AP1S2 Is Mutated in X-Linked Dandy&Ndash;Walker Malformation with Intellectual Disability, Basal Ganglia Disease and Seizure European Journal of Human Genetics (2014) 22, 363–368 & 2014 Macmillan Publishers Limited All rights reserved 1018-4813/14 www.nature.com/ejhg ARTICLE AP1S2 is mutated in X-linked Dandy–Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome) Pierre Cacciagli1,2,3, Jean-Pierre Desvignes1,2, Nadine Girard4, Marc Delepine5, Diana Zelenika5, Mark Lathrop5,6, Nicolas Le´vy1,2,3, David H Ledbetter7, William B Dobyns8 and Laurent Villard*,1,2 MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy–Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426 þ 1G4T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity. European Journal of Human Genetics (2014) 22, 363–368; doi:10.1038/ejhg.2013.135; published online 12 June 2013 Keywords: AP1S2; brain pathology; cerebral calcifications; Dandy–Walker malformation; intellectual disability; X-linked INTRODUCTION Pettigrew syndrome was mapped to Xq26 with a lod score of 2.19,4 X-linked intellectual disability (XLID) accounts for up 10% of males although a recurrence subsequent to this report showed that the with intellectual disability.1 A large number of genes whose mutations mapping data were possibly not correct. Despite several attempts to cause syndromic or nonspecific XLID have been identified during identify the causative gene, the mutation causing Pettigrew syndrome the last two decades,2 demonstrating a high degree of genetic and has remained elusive since the initial description of the condition. phenotypic heterogeneity. However, the most recent review suggested Here, we report the identification of a mutation in the AP1S2 gene— that the genetic cause of 79 syndromic forms of XLID (from an the same gene mutated in X-linked Fried syndrome—in the original estimated 160) have not yet been identified.1 X-linked Dandy–Walker Pettigrew syndrome family. We also report additional phenotype malformation with mental retardation (one would now write details for several of the affected individuals, allowing us to further ‘intellectual disability’), basal ganglia disease and seizures (MIM refine the phenotype corresponding to this XLID syndrome. 304340), also designated as MRXS5 or Pettigrew syndrome, was described 20 years ago in a four generation family including nine MATERIALS AND METHODS affected individuals.3 Patients had facial dysmorphism with a long and Ethical statement narrow face, intellectual disability, Dandy–Walker malformation (but A prior study of this family4 was approved by the Institutional Review Board at see results below) and inconstant choreoathetosis. Four individuals Baylor College of Medicine. Here we studied one affected individual (V.1) and had iron deposition in the basal ganglia seen on MRI or at autopsy. his parents, who provided updated medical history on several relatives first Head circumference was highly variable with both microcephaly reported in prior publications. Informed consent was obtained from the new and macrocephaly being reported in affected individuals from the patient and both parents. The study was approved by the Institutional Review original family. Board at Seattle Children’s Hospital (IRB #13 291). Lymphoblastoid cell lines 1Inserm, U910, Faculte´ de Me´decine de La Timone, Marseille, France; 2Aix Marseille Universite´, Faculte´ de Me´decine, Marseille, France; 3Assistance Publique Hoˆpitaux de Marseille, De´partement de Ge´ne´ tique Me´ dicale et de Biologie Cellulaire, Hoˆpital d’Enfants de La Timone, Marseille, France; 4Assistance Publique Hoˆpitaux de Marseille, Service de Neuroradiologie, Hoˆ pital de La Timone, Marseille, France; 5Commissariat a` l’Energie Atomique, Institut Ge´nomique, Centre National de Ge´notypage, Evry, France; 6Fondation Jean Dausset - CEPH, Paris, France; 7Geisinger Health System, Danville, PA, USA; 8Departments of Pediatrics and Neurology, University of Washington, Center for Integrative Brain Research, Seattle Children’s Hospital, Seattle, Washington, USA *Correspondence: Professor L Villard, Inserm U910 Faculte´ de Me´decine de La Timone, 27 bd Jean Moulin, Marseille 13385, France. Tel: þ 33 (0)491324903; Fax: þ 33 (0)491804319; E-mail: [email protected] Received 11 January 2013; revised 14 May 2013; accepted 15 May 2013; published online 12 June 2013 AP1S2 cause Pettigrew syndrome PCacciagliet al 364 from individuals III.2, III.14, IV.4 and III.3b were obtained from the Coriell patient’s RNA (see above). Primers used were located in exon 3 of the Cell Line Repository (Camden, NJ, USA; catalog numbers: GM12523, gene (forward, 50-CTGTGCTATTGAGGATCAGG-30)andexon5(reverse, GM12534, GM12542 and GM12543). 50-CATCATCTTACACCATGAGC-30) producing a 368-bp PCR product in a control cDNA and a 230-bp PCR product in the patient cDNA (Figure 3b, left Exome sequencing and reference sequence panel); or located in exon 4 of the gene (forward, 50-CTTAAAGCAATTGAG- 0 0 0 The exonic sequences were captured with the Agilent Sure Select Human CAGGC-3 )andexon5(reverse,5-CATCATCTTACACCATGAGC-3 )producing Exome V3 kit (Agilent, Santa Clara, CA, USA) and sequencing was performed on a 178-bp PCR product in control cDNA and no amplification in patient cDNA an Illumina HiSeq2000 sequencing apparatus(Illumina,SanDiego,CA,USA) (Figure 3b, right panel). The program included an initial denaturation (94 1C, used with pipeline version 1.5 at Centre National de Ge´notypage (Evry, France). 3 min) followed by 35 cycles of 94 1C for 30 s, 60 1C for 30 s and 72 1C for 30 s. Sequences were mapped on human genome build hg19 with the commercial tool CLC Genomics Workbench version 4.9 (CLCBIO, Aarhus, Denmark). The SNP RESULTS detection was also performed with CLCBIO. We kept variants with a minimum Clinical findings quality of 30 and a minimum average quality of surrounding bases of 20. The The pedigree of the original Pettigrew syndrome family is presented in AP1S2 mutation is numbered according to reference sequence NM_003916.3. The Figure 1, modified only slightly from the original published pedigree. AP1S2 mutation was submitted to the corresponding LOVD database at http:// databases.lovd.nl/shared/variants/0000017199. Patient III.8. This man had early developmental delay, poor feeding and lethargy or reduced activity (‘listless’) in infancy. He walked at 26 RNA extraction and reverse transcription months, learned to use a few words in childhood that he later lost, Total RNA was extracted from the lymphoblastoid cell lines of two affected and had no self help skills. He developed self-abusive behaviors, males (III.2 and III.14), one unaffected male (IV.4) and one carrier mother mostly slapping himself. Examination showed mildly coarse facial (III.3b) using PerfectPure RNA Tissue kit (5 PRIME GmbH, Hamburg, features (see Figure 2d in Pettigrew et al3). He became increasingly Germany) according to the instructions of the manufacturer. The RNA preparations were analyzed for purity using the ND-1000 spectrophotometer spastic, developed slow athetoid movements, severe scoliosis and (NanoDrop, Wilmington, DE, USA). Reverse transcription of 2 mgoftotal proximal contractures and was bedridden by his early 20s. At that age, RNA was performed in 20 ml of Superscript II reaction buffer (Invitrogen his height was 175 cm (40th percentile) and OFC 50.1 cm (about –4 Corp., Carlsbad, CA, USA) containing 0.2 M dithiothreitol, 250 ng of dN6, 40 U standard deviations). He had the onset of seizures at about of Rnase inhibitor (Invitrogen Corp.), 10 mM dNTP and 200 U of Superscript 31 years and died, probably in his mid- to late 30’s. At autopsy, the II reverse transcriptase (Invitrogen Corp.). frontal lobes were unusually small with a decreased neuron number. Excess iron was present in glial cells of the putamen and globus Classical PCR and sequencing pallidus of the basal ganglia and in the substantia nigra, red nuclei To amplify the region containing the c.426 þ 1G4T mutation (exon 4) on and dentate nuclei. Axonal dystrophy was noted in the cerebellum genomic DNA, we performed PCR reactions in a total volume of 50 ml, and cerebrum. Iron was noted in the atrophic skeletal muscles, and containing 1 Â PCR buffer, 0.2 mM dNTPs, 1.5 mM MgCl2,1UTaq hemosiderosis of the liver and spleen was present. polymerase, 200 nM of each primer and 50 ng of genomic DNA. The primers 0 0 used were located in intron 3 (forward, 5 -AGAGCCCAGTCTTATTTAGC-3 ) Patient III.14. This man had developmental delay, hypotonia, poor 0 0 and intron 5 (reverse, 5 -ATGGACACTACATGACAAGC-3 )ofAP1S2 head control and truncal ataxia in infancy. He walked at 2 years and producing a 480-bp PCR product. The program included an initial 1 1 1 used his first words at 18 months.
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