Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler syndrome).
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.
Meyer
Esther
E
Department of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Birmingham, B15 2TT, UK.
Ricketts
Christopher
C
Morgan
Neil V
NV
Morris
Mark R
MR
Pasha
Shanaz
S
Tee
Louise J
LJ
Rahman
Fatimah
F
Bazin
Anne
A
Bessières
Bettina
B
Déchelotte
Pierre
P
Yacoubi
Mohamed T
MT
Al-Adnani
Mudher
M
Marton
Tamas
T
Tannahill
David
D
Trembath
Richard C
RC
Fallet-Bianco
Catherine
C
Cox
Phillip
P
Williams
Denise
D
Maher
Eamonn R
ER
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*
C492690:FLVCR1 protein, human; D026901:Membrane Transport Proteins; D011991:Receptors, Virus; D004247:DNA