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FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.

Simonis N, Migeotte I, Lambert N, Perazzolo C, de Silva DC, Dimitrov B, Heinrichs C, Janssens S, Kerr B, Mortier G, Van Vliet G, Lepage P, Casimir G, Abramowicz M, Smits G, Vilain C - J. Med. Genet. (2013)

Bottom Line: Strikingly, among the six novel mutations, three are located in close proximity to the ATP's phosphates or the coordinating magnesium, with one position required for kinase activity, and three are adjacent to known mutations involved in Kallmann syndrome plus other developmental anomalies.Dominant or recessive FGFR1 mutations are responsible for Hartsfield syndrome, consistent with the known roles of FGFR1 in vertebrate ontogeny and conditional Fgfr1-deficient mice.Our study shows that, in humans, lack of accurate FGFR1 activation can disrupt both brain and hand/foot midline development, and that FGFR1 loss-of-function mutations are responsible for a wider spectrum of clinical anomalies than previously thought, ranging in severity from seemingly isolated hypogonadotropic hypogonadism, through Kallmann syndrome with or without additional features, to Hartsfield syndrome at its most severe end.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Bioinformatique des Génomes et des Réseaux (BiGRe), Université Libre de Bruxelles (ULB), Brussels, Belgium.

ABSTRACT

Background: Harstfield syndrome is the rare and unique association of holoprosencephaly (HPE) and ectrodactyly, with or without cleft lip and palate, and variable additional features. All the reported cases occurred sporadically. Although several causal genes of HPE and ectrodactyly have been identified, the genetic cause of Hartsfield syndrome remains unknown. We hypothesised that a single key developmental gene may underlie the co-occurrence of HPE and ectrodactyly.

Methods: We used whole exome sequencing in four isolated cases including one case-parents trio, and direct Sanger sequencing of three additional cases, to investigate the causative variants in Hartsfield syndrome.

Results: We identified a novel FGFR1 mutation in six out of seven patients. Affected residues are highly conserved and are located in the extracellular binding domain of the receptor (two homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Strikingly, among the six novel mutations, three are located in close proximity to the ATP's phosphates or the coordinating magnesium, with one position required for kinase activity, and three are adjacent to known mutations involved in Kallmann syndrome plus other developmental anomalies.

Conclusions: Dominant or recessive FGFR1 mutations are responsible for Hartsfield syndrome, consistent with the known roles of FGFR1 in vertebrate ontogeny and conditional Fgfr1-deficient mice. Our study shows that, in humans, lack of accurate FGFR1 activation can disrupt both brain and hand/foot midline development, and that FGFR1 loss-of-function mutations are responsible for a wider spectrum of clinical anomalies than previously thought, ranging in severity from seemingly isolated hypogonadotropic hypogonadism, through Kallmann syndrome with or without additional features, to Hartsfield syndrome at its most severe end.

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Related in: MedlinePlus

Mapping of mutations G490R, D623Y, N628K, and C725Y on FGFR1 tyrosine kinase domain crystal structure. Protein Data Bank structure 3GQI41 showing the intracellular kinase domain of FGFR1 (residues 464–770) in ribbon representation. The lower left part shows the details of the crystal structure surrounding the ATP binding pocket in the intracellular kinase domain of FGFR1. G490, D623, and N628 are in close proximity to the ATP's phosphates or coordinating magnesium. The lower right part shows the involvement of cysteine 725 in the positioning of the αG-containing segment, along with T726, P722, and K721. Substitution of the cysteine 725 by a tyrosine will likely affect the conformation of this region.27 The ATP analogue (AMPPCP) and wild-type residues of positions 490, 623, 628 and 721, 722, 725 and 726 are pictured in stick representation. Nitrogen, oxygen, phosphorus, and magnesium atoms are coloured blue, red, orange, and green, respectively. These pictures were made using UCSF Chimera.40
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JMEDGENET2013101603F3: Mapping of mutations G490R, D623Y, N628K, and C725Y on FGFR1 tyrosine kinase domain crystal structure. Protein Data Bank structure 3GQI41 showing the intracellular kinase domain of FGFR1 (residues 464–770) in ribbon representation. The lower left part shows the details of the crystal structure surrounding the ATP binding pocket in the intracellular kinase domain of FGFR1. G490, D623, and N628 are in close proximity to the ATP's phosphates or coordinating magnesium. The lower right part shows the involvement of cysteine 725 in the positioning of the αG-containing segment, along with T726, P722, and K721. Substitution of the cysteine 725 by a tyrosine will likely affect the conformation of this region.27 The ATP analogue (AMPPCP) and wild-type residues of positions 490, 623, 628 and 721, 722, 725 and 726 are pictured in stick representation. Nitrogen, oxygen, phosphorus, and magnesium atoms are coloured blue, red, orange, and green, respectively. These pictures were made using UCSF Chimera.40

Mentions: We identified three heterozygous mutations affecting amino acid residues located in the ATP binding pocket of the intracellular tyrosine kinase domain (TKD, amino acids 478–767): G490R (patient 3, moderate phenotype), D623Y (patient 4, mild phenotype), and N628K (patient 5, moderate phenotype). Analysis of the available crystallographic structures shows that the mutated amino acids are in close proximity to the ATP and the coordinating magnesium, suggesting impairment of FGFR1 kinase activity (figure 3). In support of this hypothesis, D623 is known to be required for catalysis.25 A tyrosine substitution would prevent it from fulfilling its role as a proton acceptor for the substrate. Adjacent mutations H621R, R622G, R622Q, and R622X provoke syndromic KS, some patients having corpus callosum agenesis (H621R), digit number anomalies (H621R) or fusion of metacarpal bones (R622G) (figure 4, see online supplementary table S3).20–2226


FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly.

Simonis N, Migeotte I, Lambert N, Perazzolo C, de Silva DC, Dimitrov B, Heinrichs C, Janssens S, Kerr B, Mortier G, Van Vliet G, Lepage P, Casimir G, Abramowicz M, Smits G, Vilain C - J. Med. Genet. (2013)

Mapping of mutations G490R, D623Y, N628K, and C725Y on FGFR1 tyrosine kinase domain crystal structure. Protein Data Bank structure 3GQI41 showing the intracellular kinase domain of FGFR1 (residues 464–770) in ribbon representation. The lower left part shows the details of the crystal structure surrounding the ATP binding pocket in the intracellular kinase domain of FGFR1. G490, D623, and N628 are in close proximity to the ATP's phosphates or coordinating magnesium. The lower right part shows the involvement of cysteine 725 in the positioning of the αG-containing segment, along with T726, P722, and K721. Substitution of the cysteine 725 by a tyrosine will likely affect the conformation of this region.27 The ATP analogue (AMPPCP) and wild-type residues of positions 490, 623, 628 and 721, 722, 725 and 726 are pictured in stick representation. Nitrogen, oxygen, phosphorus, and magnesium atoms are coloured blue, red, orange, and green, respectively. These pictures were made using UCSF Chimera.40
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756455&req=5

JMEDGENET2013101603F3: Mapping of mutations G490R, D623Y, N628K, and C725Y on FGFR1 tyrosine kinase domain crystal structure. Protein Data Bank structure 3GQI41 showing the intracellular kinase domain of FGFR1 (residues 464–770) in ribbon representation. The lower left part shows the details of the crystal structure surrounding the ATP binding pocket in the intracellular kinase domain of FGFR1. G490, D623, and N628 are in close proximity to the ATP's phosphates or coordinating magnesium. The lower right part shows the involvement of cysteine 725 in the positioning of the αG-containing segment, along with T726, P722, and K721. Substitution of the cysteine 725 by a tyrosine will likely affect the conformation of this region.27 The ATP analogue (AMPPCP) and wild-type residues of positions 490, 623, 628 and 721, 722, 725 and 726 are pictured in stick representation. Nitrogen, oxygen, phosphorus, and magnesium atoms are coloured blue, red, orange, and green, respectively. These pictures were made using UCSF Chimera.40
Mentions: We identified three heterozygous mutations affecting amino acid residues located in the ATP binding pocket of the intracellular tyrosine kinase domain (TKD, amino acids 478–767): G490R (patient 3, moderate phenotype), D623Y (patient 4, mild phenotype), and N628K (patient 5, moderate phenotype). Analysis of the available crystallographic structures shows that the mutated amino acids are in close proximity to the ATP and the coordinating magnesium, suggesting impairment of FGFR1 kinase activity (figure 3). In support of this hypothesis, D623 is known to be required for catalysis.25 A tyrosine substitution would prevent it from fulfilling its role as a proton acceptor for the substrate. Adjacent mutations H621R, R622G, R622Q, and R622X provoke syndromic KS, some patients having corpus callosum agenesis (H621R), digit number anomalies (H621R) or fusion of metacarpal bones (R622G) (figure 4, see online supplementary table S3).20–2226

Bottom Line: Strikingly, among the six novel mutations, three are located in close proximity to the ATP's phosphates or the coordinating magnesium, with one position required for kinase activity, and three are adjacent to known mutations involved in Kallmann syndrome plus other developmental anomalies.Dominant or recessive FGFR1 mutations are responsible for Hartsfield syndrome, consistent with the known roles of FGFR1 in vertebrate ontogeny and conditional Fgfr1-deficient mice.Our study shows that, in humans, lack of accurate FGFR1 activation can disrupt both brain and hand/foot midline development, and that FGFR1 loss-of-function mutations are responsible for a wider spectrum of clinical anomalies than previously thought, ranging in severity from seemingly isolated hypogonadotropic hypogonadism, through Kallmann syndrome with or without additional features, to Hartsfield syndrome at its most severe end.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Bioinformatique des Génomes et des Réseaux (BiGRe), Université Libre de Bruxelles (ULB), Brussels, Belgium.

ABSTRACT

Background: Harstfield syndrome is the rare and unique association of holoprosencephaly (HPE) and ectrodactyly, with or without cleft lip and palate, and variable additional features. All the reported cases occurred sporadically. Although several causal genes of HPE and ectrodactyly have been identified, the genetic cause of Hartsfield syndrome remains unknown. We hypothesised that a single key developmental gene may underlie the co-occurrence of HPE and ectrodactyly.

Methods: We used whole exome sequencing in four isolated cases including one case-parents trio, and direct Sanger sequencing of three additional cases, to investigate the causative variants in Hartsfield syndrome.

Results: We identified a novel FGFR1 mutation in six out of seven patients. Affected residues are highly conserved and are located in the extracellular binding domain of the receptor (two homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Strikingly, among the six novel mutations, three are located in close proximity to the ATP's phosphates or the coordinating magnesium, with one position required for kinase activity, and three are adjacent to known mutations involved in Kallmann syndrome plus other developmental anomalies.

Conclusions: Dominant or recessive FGFR1 mutations are responsible for Hartsfield syndrome, consistent with the known roles of FGFR1 in vertebrate ontogeny and conditional Fgfr1-deficient mice. Our study shows that, in humans, lack of accurate FGFR1 activation can disrupt both brain and hand/foot midline development, and that FGFR1 loss-of-function mutations are responsible for a wider spectrum of clinical anomalies than previously thought, ranging in severity from seemingly isolated hypogonadotropic hypogonadism, through Kallmann syndrome with or without additional features, to Hartsfield syndrome at its most severe end.

Show MeSH
Related in: MedlinePlus