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

Autor: Hatem El-Shanti, Yasser Al-Sarraj, Tawfeg Ben-Omran, Hala Boulos, Rachid C. Maroun, Rehab Ali, Khaoula Errafii, Patrick A. Curmi, Marios Kambouris
Přispěvatelé: Qatar Biomedical Research Institute (QBRI), Structure et activité des biomolécules normales et pathologiques (SABNP), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Weill Cornell Medical College in Qatar (WCMC-Q), Weill Cornell Medicine [Qatar], University of Iowa [Iowa City], Hamad Medical Corporation [Doha, Qatar], Shafallah Medical Genetics Center, Maciejak, Olek
Rok vydání: 2014
Předmět:
Male
Candidate gene
genetic structures
0302 clinical medicine
Next generation exome sequencing
Genetics(clinical)
Pharmacology (medical)
Child
Exome
Genetics (clinical)
Exome sequencing
Medicine(all)
Genetics
Zinc finger
0303 health sciences
Zinc Fingers
Syndrome
General Medicine
musculoskeletal system
Disease gene identification
Pedigree
Cognitive impairment
Mutation (genetic algorithm)
Zinc finger proteins
medicine.symptom
congenital
hereditary
and neonatal diseases and abnormalities
Molecular Sequence Data
Genes
Recessive
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Biology
Next generation exomesequencing
In-silico protein modeling
03 medical and health sciences
Camptodactyly
Gene mapping
Homozygosity mapping
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
medicine
Humans
Abnormalities
Multiple
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Amino Acid Sequence
030304 developmental biology
Sequence Homology
Amino Acid
Research
eye diseases
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Mutation
Cognition Disorders
030217 neurology & neurosurgery
Zdroj: Orphanet Journal of Rare Diseases
Orphanet Journal of Rare Diseases, BioMed Central, 2014, 9 (1), pp.80. ⟨10.1186/1750-1172-9-80⟩
Orphanet Journal of Rare Diseases, 2014, 9 (1), pp.80. ⟨10.1186/1750-1172-9-80⟩
ISSN: 1750-1172
Popis: 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.
Databáze: OpenAIRE
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