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Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex AP1S2 are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia
  1. Yoann Saillour (saillour{at}cochin.inserm.fr)
  1. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
    1. Ginevra Zanni (zianni{at}cochin.inserm.fr)
    1. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
      1. Vincent Des Portes
      1. Service de neurologie Pédiatrique, Hopital Debrousse, Lyon, France
        1. Delphine Heron
        1. Département de Génétique, GH Pitié Salpétrière, Paris, France
          1. Laurent Guibaud
          1. Service de radiologie, Hôpital Debrousse, Lyon, France
            1. Marie Théèse Iba-Zizen
            1. Service de radiologie, Hôpital des Quinze-Vingts, Paris, France
              1. Jean Louis Pedespan
              1. Service de Neurologie pédiatrique, CHU de Bordeaux, Bordeaux, France
                1. Karine Poirier (poirier{at}cochin.inserm.fr)
                1. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
                  1. Laetitia Castelneau (castelneau{at}cochin.inserm.fr)
                  1. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
                    1. Cedric Julien (julien{at}cochin.inserm.fr)
                    1. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
                      1. C Franconnet
                      1. Cytogenetique Medicale, CHU et Faculté de Médecine, Clermont-Ferrand, France
                        1. David T Bonthron
                        1. Leeds Institute of Molecular Medicine, University of Leeds, United Kingdom
                          1. M ME Porteous
                          1. South east of Scotland genetic Service, Western General Hospital, Crewe Rd, Edinburgh, United Kingdom
                            1. Jamel Chelly (chelly{at}cochin.inserm.fr)
                            1. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France
                              1. Thierry Bienvenu (bienvenu{at}cochin.inserm.fr)
                              1. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France

                                Abstract

                                Fried syndrome, first described in 1972, is a rare X-linked mental retardation that has been mapped by linkage to Xp22. Clinical characteristics include mental retardation, mild facial dysmorphism, calcifications of basal ganglia and hydrocephalus. Here we report a large four-generation family where the affected males have striking clinical features of Fried syndrome. We investigated the family for linkage to X chromosome markers, and showed that the gene for this condition lies within the interval DXS7109-DXS7593 in Xp22.2. We screened for mutations sixty candidate genes located in this region including AP1S2 shown recently to be involved in mental retardation. We found a mutation in the third intron of AP1S2 in all affected males in the large French family. We showed that the mutation resulted in skipping of exon 3, predicting a protein with 3 novel amino-acids and with termination at codon 64. Moreover, we reinvestigated at the molecular level the first known large Scottish family affected by Fried syndrome and we found a new non-sense mutation p.Gln66X in exon 3. We observed by CT scan analysis in all analysed affected patients from our French family marked calcifications of the basal ganglia, as previously observed in the first Scottish family, suggesting that the presence of distinctive basal ganglia calcification is an essential parameter to recognize this syndromic disorder. The presence of this parameter would be interesting to identify the X-linked mental retadation families which should be screened for mutations in AP1S2.

                                • AP1S2
                                • adaptor complexes
                                • calcification of the basal ganglia
                                • hydrocephalus
                                • mental retardation

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