title: Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler syndrome).
abstract: Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH), also known as Fowler syndrome, is an autosomal-recessively inherited prenatal lethal disorder characterized by hydranencephaly; brain stem, basal ganglia, and spinal cord diffuse clastic ischemic lesions with calcifications; glomeruloid vasculopathy of the central nervous system and retinal vessels; and a fetal akinesia deformation sequence (FADS) with muscular neurogenic atrophy. To identify the molecular basis for Fowler syndrome, we performed autozygosity mapping studies in three consanguineous families. The results of SNP microarrays and microsatellite marker genotyping demonstrated linkage to chromosome 14q24.3. Direct sequencing of candidate genes within the target interval revealed five different germline mutations in FLVCR2 in five families with Fowler syndrome. FLVCR2 encodes a transmembrane transporter of the major facilitator superfamily (MFS) hypothesized to be involved in regulation of growth, calcium exchange, and homeostasis. This is the first gene to be associated with Fowler syndrome, and this finding provides a basis for further studies to elucidate the pathogenetic mechanisms and phenotypic spectrum of associated disorders.
authors.affiliation: Department of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.forename: Christopher
authors.initials: C
authors.lastname: Ricketts
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.forename: Mark R
authors.initials: MR
authors.lastname: Morris
authors.forename: Shanaz
authors.initials: S
authors.lastname: Pasha
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Tee
authors.forename: Fatimah
authors.initials: F
authors.lastname: Rahman
authors.forename: Anne
authors.initials: A
authors.lastname: Bazin
authors.forename: Bettina
authors.initials: B
authors.lastname: Bessières
authors.forename: Pierre
authors.initials: P
authors.lastname: Déchelotte
authors.forename: Mohamed T
authors.initials: MT
authors.lastname: Yacoubi
authors.forename: Mudher
authors.initials: M
authors.lastname: Al-Adnani
authors.forename: Tamas
authors.initials: T
authors.lastname: Marton
authors.forename: David
authors.initials: D
authors.lastname: Tannahill
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Catherine
authors.initials: C
authors.lastname: Fallet-Bianco
authors.forename: Phillip
authors.initials: P
authors.lastname: Cox
authors.forename: Denise
authors.initials: D
authors.lastname: Williams
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D003241:Consanguinity; D017124:Conserved Sequence; D004247:DNA / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D018095:Germ-Line Mutation; D006801:Humans; D006832:Hydranencephaly / Q000235:genetics*; D006849:Hydrocephalus / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D014652:Vascular Diseases / Q000235:genetics*
chemical_list: C492690:FLVCR1 protein, human; D026901:Membrane Transport Proteins; D011991:Receptors, Virus; D004247:DNA