Limits...
Limb body wall complex, amniotic band sequence, or new syndrome caused by mutation in IQ Motif containing K (IQCK)?

Kruszka P, Uwineza A, Mutesa L, Martinez AF, Abe Y, Zackai EH, Ganetzky R, Chung B, Stevenson RE, Adelstein RS, Ma X, Mullikin JC, Hong SK, Muenke M - Mol Genet Genomic Med (2015)

Bottom Line: Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC.Human wild-type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish.This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health Bethesda, Maryland.

ABSTRACT
Limb body wall complex (LBWC) and amniotic band sequence (ABS) are multiple congenital anomaly conditions with craniofacial, limb, and ventral wall defects. LBWC and ABS are considered separate entities by some, and a continuum of severity of the same condition by others. The etiology of LBWC/ABS remains unknown and multiple hypotheses have been proposed. One individual with features of LBWC and his unaffected parents were whole exome sequenced and Sanger sequenced as confirmation of the mutation. Functional studies were conducted using morpholino knockdown studies followed by human mRNA rescue experiments. Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC. Morpholino knockdown of iqck mRNA in the zebrafish showed ventral defects including failure of ventral fin to develop and cardiac edema. Human wild-type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish. This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome.

No MeSH data available.


Related in: MedlinePlus

(A) Sanger sequencing chromatograms show IQCK wild-type sequence found in parents of patient 1 and the heterozygous missense mutation found in patient 1; (B) Protein sequence alignment of human IQCK with several IQ motif-containing proteins show absolute conservation of the glutamine (Q) residue across species (denoted by an asterisk). This is residue found mutated in our patient (p.Q223E). Pa: Pongo abelii (Sumatran orangutan); At: Arabidopsis thaliana (Mouse-ear cress); Dr: Danio rerio (Zebrafish); Bt: Bos taurus (Bovine); Xl: Xenopus laevis (African clawed frog); Hs: Homo sapiens (Human); Rn: Rattus norvegicus (Rat); Mm: Mus musculus (Mouse). The gene symbol is indicated between vertical lines, with the numbers indicating the amino acid positions in the reference isoform of the protein (isoform 1). Sequence alignment was performed using the CrustalW2 tool from EMBL-EBI (http://www.ebi.ac.uk/Tools/msa/clustalw2).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585450&req=5

fig05: (A) Sanger sequencing chromatograms show IQCK wild-type sequence found in parents of patient 1 and the heterozygous missense mutation found in patient 1; (B) Protein sequence alignment of human IQCK with several IQ motif-containing proteins show absolute conservation of the glutamine (Q) residue across species (denoted by an asterisk). This is residue found mutated in our patient (p.Q223E). Pa: Pongo abelii (Sumatran orangutan); At: Arabidopsis thaliana (Mouse-ear cress); Dr: Danio rerio (Zebrafish); Bt: Bos taurus (Bovine); Xl: Xenopus laevis (African clawed frog); Hs: Homo sapiens (Human); Rn: Rattus norvegicus (Rat); Mm: Mus musculus (Mouse). The gene symbol is indicated between vertical lines, with the numbers indicating the amino acid positions in the reference isoform of the protein (isoform 1). Sequence alignment was performed using the CrustalW2 tool from EMBL-EBI (http://www.ebi.ac.uk/Tools/msa/clustalw2).

Mentions: Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E in Patient 1. This occurs in a conserved amino acid in the IQ domain of IQCK. This variant was verified by Sanger sequencing (Fig.5A) in the proband but was absent in both parents. Multiple prediction models were used to evaluate the potential pathogenicity of the variant, including a Combined Annotation-Dependent Depletion (CADD) score of 39.0, a Grantham score of 29, a genomic evolutionary rate profiling (GERP) score of 5.6, and a PolyPhen-2 (Polymorphism Phenotyping v2) prediction of “probably damaging.” This mutation was not found in multiple databases including 1000 Genomes, the Exome Aggregation Consortium (ExAC), and the NHLBI Exome Sequencing Project (ESP).


Limb body wall complex, amniotic band sequence, or new syndrome caused by mutation in IQ Motif containing K (IQCK)?

Kruszka P, Uwineza A, Mutesa L, Martinez AF, Abe Y, Zackai EH, Ganetzky R, Chung B, Stevenson RE, Adelstein RS, Ma X, Mullikin JC, Hong SK, Muenke M - Mol Genet Genomic Med (2015)

(A) Sanger sequencing chromatograms show IQCK wild-type sequence found in parents of patient 1 and the heterozygous missense mutation found in patient 1; (B) Protein sequence alignment of human IQCK with several IQ motif-containing proteins show absolute conservation of the glutamine (Q) residue across species (denoted by an asterisk). This is residue found mutated in our patient (p.Q223E). Pa: Pongo abelii (Sumatran orangutan); At: Arabidopsis thaliana (Mouse-ear cress); Dr: Danio rerio (Zebrafish); Bt: Bos taurus (Bovine); Xl: Xenopus laevis (African clawed frog); Hs: Homo sapiens (Human); Rn: Rattus norvegicus (Rat); Mm: Mus musculus (Mouse). The gene symbol is indicated between vertical lines, with the numbers indicating the amino acid positions in the reference isoform of the protein (isoform 1). Sequence alignment was performed using the CrustalW2 tool from EMBL-EBI (http://www.ebi.ac.uk/Tools/msa/clustalw2).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585450&req=5

fig05: (A) Sanger sequencing chromatograms show IQCK wild-type sequence found in parents of patient 1 and the heterozygous missense mutation found in patient 1; (B) Protein sequence alignment of human IQCK with several IQ motif-containing proteins show absolute conservation of the glutamine (Q) residue across species (denoted by an asterisk). This is residue found mutated in our patient (p.Q223E). Pa: Pongo abelii (Sumatran orangutan); At: Arabidopsis thaliana (Mouse-ear cress); Dr: Danio rerio (Zebrafish); Bt: Bos taurus (Bovine); Xl: Xenopus laevis (African clawed frog); Hs: Homo sapiens (Human); Rn: Rattus norvegicus (Rat); Mm: Mus musculus (Mouse). The gene symbol is indicated between vertical lines, with the numbers indicating the amino acid positions in the reference isoform of the protein (isoform 1). Sequence alignment was performed using the CrustalW2 tool from EMBL-EBI (http://www.ebi.ac.uk/Tools/msa/clustalw2).
Mentions: Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E in Patient 1. This occurs in a conserved amino acid in the IQ domain of IQCK. This variant was verified by Sanger sequencing (Fig.5A) in the proband but was absent in both parents. Multiple prediction models were used to evaluate the potential pathogenicity of the variant, including a Combined Annotation-Dependent Depletion (CADD) score of 39.0, a Grantham score of 29, a genomic evolutionary rate profiling (GERP) score of 5.6, and a PolyPhen-2 (Polymorphism Phenotyping v2) prediction of “probably damaging.” This mutation was not found in multiple databases including 1000 Genomes, the Exome Aggregation Consortium (ExAC), and the NHLBI Exome Sequencing Project (ESP).

Bottom Line: Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC.Human wild-type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish.This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health Bethesda, Maryland.

ABSTRACT
Limb body wall complex (LBWC) and amniotic band sequence (ABS) are multiple congenital anomaly conditions with craniofacial, limb, and ventral wall defects. LBWC and ABS are considered separate entities by some, and a continuum of severity of the same condition by others. The etiology of LBWC/ABS remains unknown and multiple hypotheses have been proposed. One individual with features of LBWC and his unaffected parents were whole exome sequenced and Sanger sequenced as confirmation of the mutation. Functional studies were conducted using morpholino knockdown studies followed by human mRNA rescue experiments. Using whole exome sequencing, a de novo heterozygous mutation was found in the gene IQCK: c.667C>G; p.Q223E and confirmed by Sanger sequencing in an individual with LBWC. Morpholino knockdown of iqck mRNA in the zebrafish showed ventral defects including failure of ventral fin to develop and cardiac edema. Human wild-type IQCK mRNA rescued the zebrafish phenotype, whereas human p.Q223E IQCK mRNA did not, but worsened the phenotype of the morpholino knockdown zebrafish. This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome.

No MeSH data available.


Related in: MedlinePlus