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

Marios Kambouris, Rachid C. Maroun, Tawfeg Ben-Omran, Yaser Al-Sarraj, Khaoula Errafii, Rehab Ali, Hala Boulos, Patrick A. Curmi, Hatem El-Shanti

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number80
JournalOrphanet Journal of Rare Diseases
Volume9
Issue number1
DOIs
Publication statusPublished - 7 Jun 2014

Fingerprint

Zinc Fingers
Mutation
Exome
Chromosome Mapping
Genes
Fingers
Failure to Thrive
Muscle Hypotonia
Metatarsal Bones
Brain
Fetal Development
Computational Biology
Serine
Ear
Mouth
Cognitive Dysfunction
Knee
Protein Isoforms
Transcription Factors
Gene Expression

Keywords

  • Cognitive impairment
  • Homozygosity mapping
  • In-silico protein modeling
  • Next generation exome sequencing
  • Zinc finger proteins

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Mutations in zinc finger 407 [ZNF407] cause a unique autosomal recessive cognitive impairment syndrome. / Kambouris, Marios; Maroun, Rachid C.; Ben-Omran, Tawfeg; Al-Sarraj, Yaser; Errafii, Khaoula; Ali, Rehab; Boulos, Hala; Curmi, Patrick A.; El-Shanti, Hatem.

In: Orphanet Journal of Rare Diseases, Vol. 9, No. 1, 80, 07.06.2014.

Research output: Contribution to journalArticle

Kambouris, Marios ; Maroun, Rachid C. ; Ben-Omran, Tawfeg ; Al-Sarraj, Yaser ; Errafii, Khaoula ; Ali, Rehab ; Boulos, Hala ; Curmi, Patrick A. ; El-Shanti, Hatem. / Mutations in zinc finger 407 [ZNF407] cause a unique autosomal recessive cognitive impairment syndrome. In: Orphanet Journal of Rare Diseases. 2014 ; Vol. 9, No. 1.
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abstract = "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.",
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AU - Kambouris, Marios

AU - Maroun, Rachid C.

AU - Ben-Omran, Tawfeg

AU - Al-Sarraj, Yaser

AU - Errafii, Khaoula

AU - Ali, Rehab

AU - Boulos, Hala

AU - Curmi, Patrick A.

AU - El-Shanti, Hatem

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N2 - 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.

AB - 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.

KW - Cognitive impairment

KW - Homozygosity mapping

KW - In-silico protein modeling

KW - Next generation exome sequencing

KW - Zinc finger proteins

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