Mutations in zinc finger 407 [ZNF407] cause a unique autosomal recessive cognitive impairment syndrome

Orphanet Journal of Rare Diseases

Hatem El-Shanti²  Patrick A Curmi⁷  Hala Boulos⁵  Rehab Ali⁴  Khaoula Errafii³  Yasser Al-Sarraj³  Tawfeg Ben-Omran⁶  Rachid C Maroun⁷  Marios Kambouris¹ 

[1] Yale University School of Medicine, Genetics, New Haven, CT, USA;University of Iowa, Pediatrics, Iowa City, IA, USA;Qatar Biomedical Research Institute, Medical Genetics Center, 69 Lusail Street, West Bay Area, P.O. Box: 33123, Doha, Qatar;Clinical & Metabolic Genetics, Pediatrics, Hamad Medical Corporation, Doha, Qatar;Shafallah Medical Genetics Center, Doha, Qatar;Weill Cornell Medical College, Doha, Qatar;Laboratoire Structure-Activité des Biomolécules Normales et Pathologiques, Institut National de la Santé et de la Recherche Médicale (INSERM), Université d’Evry Val d’Essonne, Evry 91025, France

关键词: In-silico protein modeling;    Next generation exome sequencing;    Homozygosity mapping;    Cognitive impairment;    Zinc finger proteins;   

Others  :  861641
DOI  :  10.1186/1750-1172-9-80

 received in 2013-12-11, accepted in 2014-05-29,  发布年份 2014

【 摘 要 】

Background

A consanguineous Arab family is affected by an apparently novel autosomal recessive disorder characterized by cognitive impairment, failure-to-thrive, hypotonia and dysmorphic features including bilateral ptosis and epicanthic folds, synophrys, midface hypoplasia, downturned mouth corners, thin upper vermillion border and prominent ears, bilateral 5th finger camptodactyly, bilateral short 4th metatarsal bones, and limited knee mobility bilaterally.

Methods

The family was studied by homozygosity mapping, candidate gene mutation screening and whole Exome Next Generation Sequencing of a single affected member to identify the offending gene and mutation. The mutated gene product was studied by structural bioinformatics methods.

Results

A damaging c.C5054G mutation affecting an evolutionary highly conserved amino acid p.S1685W was identified in the ZNF407 gene at 18q23. The Serine to Tryptophane mutation affects two of the three ZNF407 isoforms and is located in the last third of the protein, in a linker peptide adjoining two zinc-finger domains. Structural analyses of this mutation shows disruption of an H-bond that locks the relative spatial position of the two fingers, leading to a higher flexibility of the linker and thus to a decreased probability of binding to the target DNA sequence essentially eliminating the functionality of downstream domains and interfering with the expression of various genes under ZNF407 control during fetal brain development.

Conclusions

ZNF407 is a transcription factor with an essential role in brain development. When specific and limited in number homozygosity intervals exist that harbor the offending gene in consanguineous families, Whole Exome Sequencing of a single affected individual is an efficient approach to gene mapping and mutation identification.

【 授权许可】

   
2014 Kambouris et al.; licensee BioMed Central Ltd.

【 图 表 】

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