Homozygous mutation in CEP19, a gene mutated in morbid obesity, in Bardet-Biedl syndrome with predominant postaxial polydactyly.
J Med Genet
; 55(3): 189-197, 2018 03.
Article
en En
| MEDLINE
| ID: mdl-29127258
ABSTRACT
BACKGROUND:
Bardet-Biedl syndrome (BBS) is a ciliopathy with extensive phenotypic variability and genetic heterogeneity. We aimed to discover the gene mutated in a consanguineous kindred with multiple cases of a BBS phenotype.METHODS:
SNP genotype data were used for linkage analysis and exome sequencing to identify mutations. Modelling and in silico analysis were performed to predict mutation severity.RESULTS:
Patients had postaxial polydactyly plus variable other clinical features including rod-cone dystrophy, obesity, intellectual disability, renal malformation, developmental delay, dental anomalies, speech disorder and enlarged fatty liver. The 4.57 Mb disease locus harboured homozygous, truncating CEP19 c.194_195insA (p.Tyr65*) mutation. We also found glioma-associated oncogene homolog 1(GLI1) c.820G>C (p.Gly274Arg) in the homozygous state in most patients. In silico modelling strongly suggests that it is damaging. Also, different combinations of four possible modifier alleles in BBS-related genes were detected. Two are known modifier alleles for BBS, splicing variant CCDC28B c.330C>T and missense MKKS/BBS6 p.Ile339Val, and the others are C8ORF37/BBS21 p.Ala178Val and TMEM67/BBS14 modifier p.Asp799Asp. Some patients carry all those five known/possible modifier alleles. Such variants are highly significantly more abundant in our patients than in a control group.CONCLUSION:
CEP19 encodes a centrosomal and ciliary protein, as all BBS genes do. Another truncating mutation p.Arg82* has been reported as responsible for morbid obesity in a family; however, in the family we present, not all homozygotes are obese, although some are severely obese. The variant in GLI1, encoding a transcription factor that localises to the primary cilium and nucleus and is a mediator of the sonic hedgehog pathway, possibly exacerbates disease severity when in the homozygous state.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Obesidad Mórbida
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Dedos del Pie
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Polidactilia
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Proteínas de Ciclo Celular
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Síndrome de Bardet-Biedl
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Dedos
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Proteína con Dedos de Zinc GLI1
Tipo de estudio:
Prognostic_studies
Límite:
Adolescent
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Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
J Med Genet
Año:
2018
Tipo del documento:
Article
País de afiliación:
Turquía