Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies.
Hum Mutat
; 38(5): 540-547, 2017 05.
Article
em En
| MEDLINE
| ID: mdl-28145000
ABSTRACT
Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. Mutations in filamin B (FLNB) and MYH3 have been reported for autosomal-recessive and autosomal-dominant SCT, respectively. We present a family with two patients suffering from autosomal-recessive SCT with rib anomalies, including malalignment, crowding, and uneven size and shape of ribs. Whole-exome sequencing revealed a novel p.S2542Lfs* 82 (c.7621dup) frameshift mutation in FLNB. This frameshift mutation lies in the C-terminal-most domain involved in FLNB dimerization and resulted in a 20-residue elongation, with complete familial segregation and absence in 376 normal controls. The mutant p.S2542Lfs* 82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells. The p.S2542Lfs* 82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus. This is the first identified mutation in the dimerization domain of FLNB. This loss-of-function frameshift mutation in FLNB causes autosomal-recessive SCT with rarely reported rib anomalies. This report demonstrates the involvement of rib anomaly in SCT and its causative mutation in the dimerization domain of FLNB.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenótipo
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Escoliose
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Sinostose
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Vértebras Torácicas
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Anormalidades Múltiplas
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Doenças Musculoesqueléticas
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Domínios e Motivos de Interação entre Proteínas
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Multimerização Proteica
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Filaminas
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Genes Recessivos
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
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Prognostic_studies
Limite:
Adult
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Female
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Humans
Idioma:
En
Revista:
Hum Mutat
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Taiwan