title: Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome.
abstract: First described as a variant of Larsen syndrome in Reunion Island (LRS) in the southern Indian Ocean, 'Larsen of Reunion Island syndrome' is characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It overlaps with Desbuquois dysplasia, Larsen syndrome and spondyloepiphyseal dysplasia with dislocations ascribed to CANT1, FLNB and CHST3 mutations, respectively. We collected the samples of 22 LRS cases. After exclusion of CANT1, FLNB and CHST3 genes, an exome sequencing was performed in two affected second cousins and one unaffected sister. We identified a homozygous missense mutation in B4GALT7, NM_007255.2: c.808C>T p.(Arg270Cys) named p.R270C, in the two affected cases, not present in the unaffected sister. The same homozygous mutation was subsequently identified in the remaining 20 LRS cases. Our findings demonstrate that B4GALT7 is the causative gene for LRS. The identification of a unique homozygous mutation argues in favor of a founder effect. B4GALT7 encodes a galactosyltransferase, required for the initiation of glycoaminoglycan side chain synthesis of proteoglycans. This study expands the phenotypic spectrum of B4GALT7 mutations, initially described as responsible for the progeroid variant of Ehlers-Danlos syndrome. It further supports a common physiopathological basis involving proteoglycan synthesis in skeletal disorders with dislocations.
authors.affiliation: 1] Service de Génétique, CHU-REUNION, Centre Hospitalier Universitaire de la Réunion, Saint-Denis, France [2] Département de génétique, INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Cartault
authors.affiliation: Service de Génétique, CHU-REUNION, Centre Hospitalier Universitaire de la Réunion, Saint-Denis, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Munier
authors.affiliation: Service de Néonatologie, Centre Hospitalier Universitaire de la Réunion, Saint-Pierre, France.
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Jacquemont
authors.affiliation: Service de Génétique, CHU-REUNION, Centre Hospitalier Universitaire de la Réunion, Saint-Denis, France.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Vellayoudom
authors.affiliation: Service de Génétique, CHU-REUNION, Centre Hospitalier Universitaire de la Réunion, Saint-Denis, France.
authors.forename: Bérénice
authors.initials: B
authors.lastname: Doray
authors.affiliation: Service de Génétique, CHU-REUNION, Centre Hospitalier Universitaire de la Réunion, Saint-Denis, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Payet
authors.affiliation: Service de Néonatologie, Centre Hospitalier Universitaire de la Réunion, Saint-Pierre, France.
authors.forename: Hanitra
authors.initials: H
authors.lastname: Randrianaivo
authors.affiliation: Service de Chirurgie Infantile, Centre Hospitalier Universitaire de la Réunion, Saint-Denis, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Laville
authors.affiliation: Département de génétique, INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Département de génétique, INSERM U781, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D019066:Facies; D005260:Female; D005449:Fluorenes; D018703:Founder Effect; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics*; D005787:Gene Frequency; D006720:Homozygote; D006801:Humans; D006827:Hydantoins; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D005449:Fluorenes; D006827:Hydantoins; C045887:alconil; D005700:Galactosyltransferases; C063053:xylosylprotein 4-beta-galactosyltransferase
references.citation: Am J Hum Genet. 2009 Nov;85(5):706-10
references.pmid: 19853239
references.citation: Am J Hum Genet. 2011 May 13;88(5):608-15
references.pmid: 21549340
references.citation: J Biol Chem. 1998 Mar 20;273(12):6615-8
references.pmid: 9506957
references.citation: Am J Med Genet A. 2011 May;155A(5):943-68
references.pmid: 21438135
references.citation: J Med Genet. 1992 Jul;29(7):465-70
references.pmid: 1640425
references.citation: Am J Hum Genet. 2013 Jun 6;92(6):935-45
references.pmid: 23664118
references.citation: Nat Biotechnol. 2009 Feb;27(2):182-9
references.pmid: 19182786
references.citation: Hum Mutat. 2012 Aug;33(8):1261-6
references.pmid: 22539336
references.citation: Am J Hum Genet. 1987 Sep;41(3):436-53
references.pmid: 3631078
references.citation: Biochem J. 2010 Dec 1;432(2):303-11
references.pmid: 20809901
references.citation: J Mol Med (Berl). 2006 Jul;84(7):583-94
references.pmid: 16583246
references.citation: Am J Hum Genet. 2011 Jul 15;89(1):15-27
references.pmid: 21763480
references.citation: Am J Med Genet A. 2013 Oct;161A(10):2519-27
references.pmid: 23956117
references.citation: Clin Genet. 1971;2(2):87-90
references.pmid: 5116594
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10155-60
references.pmid: 15215498
references.citation: J Pediatr Orthop. 1994 Jan-Feb;14(1):63-73
references.pmid: 8113375
references.citation: J Pediatr. 1950 Oct;37(4):574-81
references.pmid: 14779259
references.citation: J Biol Chem. 1999 Sep 10;274(37):26165-71
references.pmid: 10473568
references.citation: J Pediatr. 1971 Feb;78(2):291-8
references.pmid: 5539773
references.citation: Int Orthop. 1979;3(1):47-53
references.pmid: 549865
references.citation: J Biol Chem. 2001 Dec 21;276(51):48189-95
references.pmid: 11551958
references.citation: Nucleic Acids Res. 2010 Sep;38(16):e164
references.pmid: 20601685
references.citation: Am J Hum Genet. 2008 Jun;82(6):1368-74
references.pmid: 18513679
references.citation: Am J Med Genet A. 2004 Jul 1;128A(1):39-45
references.pmid: 15211654
references.citation: Arch Fr Pediatr. 1975 Aug-Sep;32(7):601-7
references.pmid: 1221956
references.citation: Nat Genet. 2004 Apr;36(4):405-10
references.pmid: 14991055
references.citation: J Biol Chem. 1999 Oct 8;274(41):28841-4
references.pmid: 10506123