Dataset Information

Expansion of the Spectrum of FLNA Mutations Associated with Melnick-Needles Syndrome.

ABSTRACT: Melnick-Needles syndrome (MNS) is a rare X-linked bone dysplasia characterised by facial dysmorphology and radiographic abnormalities [Melnick and Needles, 1966;97:39-48]. Previously, all published cases of MNS were associated with only 4 mutations [Robertson et al., 2003;33:487-491; Santos et al., 2010;152A:726-731], all localised within exon 22 of FLNA, the gene encoding the cytoskeletal protein filamin A. Here we report 3 new mutations in FLNA that are associated with MNS. One affected member of the first family with the mutation p.Y1229S presented with a stroke while this patient's daughter, previously known to be affected from a young age, developed multiple sclerosis. A second unrelated patient with a typical phenotype is shown to have the mutation c.1054G>T (p.G352W) within exon 7 of FLNA. A third individual with an atypical presentation but radiological findings very similar to those seen in classic MNS has a deletion likely to affect residues within repeat domain 14. These findings indicate that the mutational spectrum for MNS is wider than previously appreciated and has implications for genetic testing strategies employed to confirm a diagnosis of this rare disorder.

SUBMITTER: Foley C

PROVIDER: S-EPMC2957847 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Expansion of the Spectrum of FLNA Mutations Associated with Melnick-Needles Syndrome.

Foley C C Roberts K K Tchrakian N N Morgan T T Fryer A A Robertson S P SP Tubridy N N

Molecular syndromology 20100914 3

Melnick-Needles syndrome (MNS) is a rare X-linked bone dysplasia characterised by facial dysmorphology and radiographic abnormalities [Melnick and Needles, 1966;97:39-48]. Previously, all published cases of MNS were associated with only 4 mutations [Robertson et al., 2003;33:487-491; Santos et al., 2010;152A:726-731], all localised within exon 22 of FLNA, the gene encoding the cytoskeletal protein filamin A. Here we report 3 new mutations in FLNA that are associated with MNS. One affected member ...[more]

PMID: 21031081

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Project description:BackgroundFilamin A, encoded by the X-linked gene FLNA, links the cell membrane with the cytoskeleton and acts as a regulator of the actin cytoskeleton. Mutations in FLNA cause a large spectrum of congenital malformations during embryonic development, including Melnick-Needles syndrome (MNS). However, reports of MNS, especially in males, are rare, and the pathogenesis molecular mechanisms are not well understood.MethodsWe found a family with two consecutive miscarriages of similar fetuses with multiple malformations. DNA was extracted from peripheral blood and tissues, and whole exome sequencing was performed for genetic analysis. Then, we created a C57BL/6 mouse with a point mutation by CRISPR/Cas-mediated genome engineering. The migration of primary abdominal muscle cell was detected by wound healing assay.ResultsThe first fetus showed congenital hygroma colli and omphalocele identified by ultrasound at 12 wks; the second fetus showed hygroma colli and thoraco abdominoschisis at 12 wks, with a new hemizygous mutation c.4420G>A in exon 26 of the FLNA gene, which is predicted to cause an amino acid substitution (p.Asp1474Asn). The mother and grandmother were both present in the c.4420G>A heterozygous state, and the mother's healthy brother had wild-type FLNA. These FLNA-mutated mice exhibited a broader central gap between the rectus abdominis than the wild type (WT), similar to the midline structure dysplasia of the abdominal wall in the two fetuses. Wound healing assays showed the attenuated migration capacity of abdominal muscle cells in mice with mutated FLNA. Finally, we summarized the cases of MNS with FLNA mutation from the accessible published literature thus far.ConclusionOur research revealed a mutation site of the FLNA for MNS and explored the mechanism of midline structure dysplasia in the abdominal wall of male patients, which could provide more evidence for the clinical diagnosis and genetic counseling of families with these disorders.

Dataset Information

Expansion of the Spectrum of FLNA Mutations Associated with Melnick-Needles Syndrome.

Publications

Expansion of the Spectrum of FLNA Mutations Associated with Melnick-Needles Syndrome.

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