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WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-?B pathway in cilia.

ABSTRACT: Short-rib polydactyly (SRP) syndrome type III, or Verma-Naumoff syndrome, is an autosomal-recessive chondrodysplasia characterized by short ribs, a narrow thorax, short long bones, an abnormal acetabulum, and numerous extraskeletal malformations and is lethal in the perinatal period. Presently, mutations in two genes, IFT80 and DYNC2H1, have been identified as being responsible for SRP type III. Via homozygosity mapping in three affected siblings, a locus for the disease was identified on chromosome 9q34.11, and homozygosity for three missense mutations in WDR34 were found in three independent families, as well as compound heterozygosity for mutations in one family. WDR34 encodes a member of the WD repeat protein family with five WD40 domains, which acts as a TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-?B activation pathway. We showed, through structural modeling, that two of the three mutations altered specific structural domains of WDR34. We found that primary cilia in WDR34 mutant fibroblasts were significantly shorter than normal and had a bulbous tip. This report expands on the pathogenesis of SRP type III and demonstrates that a regulator of the NF-?B activation pathway is involved in the pathogenesis of the skeletal ciliopathies.

SUBMITTER: Huber C

PROVIDER: S-EPMC3824112 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III.

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Genetic variations in the DYNC2H1 gene causing SRTD3 (short-rib thoracic dysplasia 3 with or without polydactyly)

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Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis.

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Project description:BackgroundShort-rib thoracic dysplasia (SRTD) and Joubert syndrome (JS) are rare genetic ciliopathies, and individuals with either syndrome can manifest cerebellar malformation and variable developmental delays. However, neither of these conditions is easily diagnosed during pregnancy due to a limited fetal phenotype. Here, we investigated a fetus that was initially observed to have short limbs and polydactyly and discovered a compound heterozygous pathogenesis through exome sequencing (ES).MethodsSimultaneous trio-ES and chromosome microarray analysis was provided for the fetus. The presence and effects of these variants on splicing were further validated at the DNA and RNA levels.ResultsOnly short limbs and post-axial polydactyly of the fetus were detected during the second trimester. Two variants (c.3940+1G>A and c.3303G>A), affecting splicing of KIAA0586, were identified from amniocytes through ES and validated by Sanger sequencing. More intensive fetal monitoring was applied, and the fetus was also found to have deformed cerebellar malformation and a constricted thoracic cage.ConclusionsHerein, we report the genetic pathogenesis of SRTD and/or JS associated with KIAA0586 in a fetus. The novel splicing variants observed expand the spectrum of KIAA0586 in SRTD and/or JS. Based on the genetic data and the distinct corresponding phenotypes discovered by imaging examination, a comprehensive diagnosis was made during pregnancy and more valuable prognostic information was provided for the parents.

| S-EPMC10009908 | biostudies-literature

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