Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene - PubMed (original) (raw)

. 2010 Jul 9;87(1):146-53.

doi: 10.1016/j.ajhg.2010.06.008.

Rowida Almomani, Emmelien Aten, Jacopo Celli, Jaap van der Heijden, Hanka Venselaar, Stephen P Robertson, Anna Baroncini, Brunella Franco, Lina Basel-Vanagaite, Emiko Horii, Ricardo Drut, Yavuz Ariyurek, Johan T den Dunnen, Martijn H Breuning

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Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene

Yu Sun et al. Am J Hum Genet. 2010.

Abstract

Terminal osseous dysplasia (TOD) is an X-linked dominant male-lethal disease characterized by skeletal dysplasia of the limbs, pigmentary defects of the skin, and recurrent digital fibroma with onset in female infancy. After performing X-exome capture and sequencing, we identified a mutation at the last nucleotide of exon 31 of the FLNA gene as the most likely cause of the disease. The variant c.5217G>A was found in six unrelated cases (three families and three sporadic cases) and was not found in 400 control X chromosomes, pilot data from the 1000 Genomes Project, or the FLNA gene variant database. In the families, the variant segregated with the disease, and it was transmitted four times from a mildly affected mother to a more seriously affected daughter. We show that, because of nonrandom X chromosome inactivation, the mutant allele was not expressed in patient fibroblasts. RNA expression of the mutant allele was detected only in cultured fibroma cells obtained from 15-year-old surgically removed material. The variant activates a cryptic splice site, removing the last 48 nucleotides from exon 31. At the protein level, this results in a loss of 16 amino acids (p.Val1724_Thr1739del), predicted to remove a sequence at the surface of filamin repeat 15. Our data show that TOD is caused by this single recurrent mutation in the FLNA gene.

Copyright 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1

The Pedigrees and the Phenotype of Family 3 (A) The pedigrees investigated in this study. In family 3, XCI patterns show the silencing of the X chromosome that carries the mutant allele. (B) The hands of 3I:2. (C) Multiple frenula of 3II:4. (D) The right hand of 3II:4. She has clinodactyly and digital fibroma. (E) The right axillary pterygium of 3II:5. (F) The right hand of 3II:5.

Figure 2

Figure 2

Genomic Structure and Mutation Analysis of FLNA (A) c.5217G>A was confirmed by Sanger sequencing in all of the patients. The unaffected family members and controls carry the homozygous normal allele. (B) The sequence of c.5850T>C in family 1. (C) FLNA is located in Xq28, the target region of linkage analysis. c.5217G>A alters the last nucleotide of exon 31 of FLNA.

Figure 3

Figure 3

Detection of Alternative Splicing and 3D Protein Model (A) Diagram of four FLNA transcripts in fibroma cells: transcripts 1 and 2, which carry the 48 bp deletion at the end of exon 31, as well as the normal transcripts 3 and 4. (B) RT-PCR result from Agilent 2100 Bioanalyzer. Lane 1 is the product of the fibroblasts of 1III:6, which has a predominant longer isoform. Lanes 2–4 and 8 are four control human fibroblasts. Lanes 5–7 show RT-PCR products that were obtained from fibroma cells of 1III:6, the normal bands from two FLNA isoforms, and two extra shorter bands, which are faint in lane 6 (left fifth finger) and lane 7 (fifth toe of the left foot), whereas lane 5 (right fifth finger) shows four dark bands. (C) Sanger sequencing results of c.5858T>C and c.5217G>A in fibroblast and fibroma cells of 1III:6. (D) The 3D model of FLNA domain 15. The deleted 16 amino acids are marked in gray. Beta strands are marked in red. Green represents a turn. Yellow indicates a 3/10 helix. Random coils are colored in cyan.

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