A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts.
Two disorders, periventricular nodular heterotopia (PVNH) and a group of skeletal dysplasias belonging to the oto-palato-digital (OPD) spectrum, are caused by FLNA mutations. They are considered mutually exclusive because of the different presumed effects of the respective FLNA gene mutations, leading to loss of function (PVNH) and gain of function (OPD), respectively. We describe here the first patient manifesting PVNH in combination with frontometaphyseal dysplasia, a skeletal dysplasia of the OPD-spectrum. A novel de novo mutation, 7315C-->A in exon 45 of the FLNA gene, was identified. It leads to two aberrant transcripts, one full-length transcript with the point mutation causing a substitution of a highly conserved leucine residue (L2439M) and a second shortened transcript lacking 21 bp due to the creation of an ectopic splice donor site in exon 45. We propose that the dual phenotype is caused by two functionally different, aberrant filamin A proteins and therefore represents an exceptional model case of allelic gain-of-function and loss-of-function phenotypes due to a single mutational event.
Zenker
Martin
M
Institute of Human Genetics, University of Erlangen-Nuremberg, Germany. mzenker@humgenet.uni-erlangen.de
Rauch
Anita
A
Winterpacht
Andreas
A
Tagariello
Andreas
A
Kraus
Cornelia
C
Rupprecht
Thomas
T
Sticht
Heinrich
H
Reis
André
A
D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001848:Bone Diseases, Developmental / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003285:Contractile Proteins / Q000737:chemistry / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D064448:Filamins; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009422:Nervous System Diseases / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D017434:Protein Structure, Tertiary
D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins