C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome.

BACKGROUND: Sensenbrenner syndrome is a heterogeneous ciliopathy that is characterised by skeletal and ectodermal anomalies, accompanied by chronic renal failure, heart defects, liver fibrosis and other features. OBJECTIVE: To identify an additional causative gene in Sensenbrenner syndrome. METHODS: Single nucleotide polymorphism array analysis and standard sequencing techniques were applied to identify the causative gene. The effect of the identified mutation on protein translation was determined by western blot analysis. Antibodies against intraflagellar transport (IFT) proteins were used in ciliated fibroblast cell lines to investigate the molecular consequences of the mutation on ciliary transport. RESULTS: Homozygosity mapping and positional candidate gene sequence analysis were performed in two siblings with Sensenbrenner syndrome of a consanguineous Moroccan family. In both siblings, a homozygous mutation in the initiation codon of C14ORF179 was identified. C14ORF179 encodes IFT43, a subunit of the IFT complex A (IFT-A) machinery of primary cilia. Western blots showed that the mutation disturbs translation of IFT43, inducing the initiation of translation of a shorter protein product from a downstream ATG. The IFT-A protein complex is implicated in retrograde ciliary transport along axonemal microtubules. It was shown that in fibroblasts of one of the siblings affected by Sensenbrenner syndrome, disruption of IFT43 disturbs this transport from the ciliary tip to its base. As anterograde transport in the opposite direction apparently remains functional, the IFT complex B proteins accumulate in the ciliary tip. Interestingly, similar results were obtained using fibroblasts from a patient with Sensenbrenner syndrome with mutations in WDR35/IFT121, encoding another IFT-A subunit. CONCLUSIONS: The results indicate that Sensenbrenner syndrome is caused by disrupted IFT-A-mediated retrograde ciliary transport.

[Mutation screening and prenatal diagnosis of hidrotic ectodermal dysplasia in a Chinese family].

OBJECTIVE: To analyze the mutations in Cx30 gene in a Chinese family with hidrotic ectodermal dysplasia (HED) and to make prenatal diagnosis on the embryo which has been pregnant for 5 months. METHODS: A family including 2 affected and 4 unaffected individuals was collected, and their informed consents were obtained. The affected woman had a five-month pregnancy. An 884 bp fragment containing the whole GJB6 coding sequence was amplified by PCR and the products were bi-direction sequenced directly. The mutation was further confirmed with restriction endoenzyme digesting. On the base of successful gene diagnosis, the following detection procedure on the pregnant baby was performed. First the whole coding region of Cx30 was amplified using primers Cx30-F and Cx30-R and the PCR products were digested by Hae II. Then the PCR products were cloned into pUCm-T vector. Blue-white blot screening method and PCR-restriction endoenzyme digesting technique were used to identify the correct clones. The mutant allele clone was sequenced to confirmed the mutation. RESULTS: A heterozygous missense mutation 263C --> T in the Cx30 gene was detected in the affected little girl and her affected mother, which led to an amino acid substitution (A88V) in the second transmembrane domain of GJB6. The mutation was confirmed by Hae II digestion. A88V mutant allele cannot be cut while the wild normal allele can be cut into two fragments, 520 and 278 bp. The result of analyse on the five-month pregnancy show the embryo carried the A88V mutation too. So the embryo will be a patient. CONCLUSION: An A88V missense mutation in the Cx30 gene can also cause HED in Chinese Han population. Based on the gene diagnosis, prenatal diagnosis can be played using bi-direction sequencing and confirmed with restriction endoenzyme digesting.

[Neuroectodermal dysplasia in 2 Uzbek families]. / Sindrom neiroektodermal'noi displazii v dvukh Uzbekskikh sem'iakh.

The authors present the clinical and genealogical description of 6 patients with neuroectodermal dysplasia diagnosed by a medical expedition party in Khankin district of the Khorezm region. Unique combination of clinical signs (total alopecia, microcephalia, oligophrenia, hyperhydrosis and hypogenitalism) helped differentiating the syndrome from other well-known hereditary neuroectodermal dysplasias. The nature of the syndrome segregation in the families suggested its autosomal-recessive mode of inheritance.

Cutaneous neonatal lupus erythematosus in Chinese neonates.

Neonatal lupus erythematosus (NLE) is a well established subset of Lupus erythematous (LE). Three chinese female neonates presented to our Skin Centre, from May 1990 to May 1991 with NLE. All had skin lesions without congenital heart block and systemic problems. Two had photosensitive annular erythematous lesions on scalp, urticarial lesions on body, and one with facial atrophy, with aplasia cutis congenita. The biopsies were non specific while one had C3 in vessel walls. The major serogical marker was anti La antibody/SSB in two babies and anti Ro antibody/SSA in one. Two mothers were known cases of LE and one, was undiagnosed. Two infants were treated with short term low dose prednisolone. The infants will require long term follow up with paediatricians, in view of the fact that they can develop SLE later. The diagnosis of NLE is emphasised in infants with facial lesions to avoid delay in diagnosis, and full work up in both infants and mother is necessary.