Limits...
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.

Show MeSH

Related in: MedlinePlus

Mapping of mutations L165S and L191S on crystal structure. Protein Data Bank structure 3OJV38 showing the extracellular Ig-like domains 2 and 3 of FGFR1 (amino acids 147–359) bound to FGF1 in surface representation, and detail around leucine 165 in ribbon representation. FGFR1 is shown in grey and FGF1 in blue. Leucines 165 and 191 are coloured in orange red. The detailed view is highlighting the interface between FGFR1 and FGF1 around leucine 165. Tyrosine 30 on FGF1 forms hydrogen bonds with leucine 165 and alanine 167.39 Substitution of the leucine 165 by a serine should affect FGF binding. These pictures were made using  UCSF Chimera.40
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3756455&req=5

JMEDGENET2013101603F2: Mapping of mutations L165S and L191S on crystal structure. Protein Data Bank structure 3OJV38 showing the extracellular Ig-like domains 2 and 3 of FGFR1 (amino acids 147–359) bound to FGF1 in surface representation, and detail around leucine 165 in ribbon representation. FGFR1 is shown in grey and FGF1 in blue. Leucines 165 and 191 are coloured in orange red. The detailed view is highlighting the interface between FGFR1 and FGF1 around leucine 165. Tyrosine 30 on FGF1 forms hydrogen bonds with leucine 165 and alanine 167.39 Substitution of the leucine 165 by a serine should affect FGF binding. These pictures were made using  UCSF Chimera.40

Mentions: In two of our patients with Hartsfield syndrome, we identified homozygous mutations affecting amino acid residues located in the extracellular ligand binding domain D2 of FGFR1: L165S, in patient 1, with a severe phenotype, and L191S, in patient 2, with a moderate phenotype (table 1, figure 1). Both parents of patient 1 were heterozygous for the L165S mutation, and were reported to be asymptomatic and spontaneously fertile. Parents of patient 2 were not available for testing. Mapping of these mutations on available FGFR1 structures from the RCSB Protein Data Bank shows that L165S is likely to affect FGF binding; the effect for L191S is less clear (figure 2). One previous KS patient has been described with a homozygous FGFR1 A167S mutation.20 This patient had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits).24


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 L165S and L191S on crystal structure. Protein Data Bank structure 3OJV38 showing the extracellular Ig-like domains 2 and 3 of FGFR1 (amino acids 147–359) bound to FGF1 in surface representation, and detail around leucine 165 in ribbon representation. FGFR1 is shown in grey and FGF1 in blue. Leucines 165 and 191 are coloured in orange red. The detailed view is highlighting the interface between FGFR1 and FGF1 around leucine 165. Tyrosine 30 on FGF1 forms hydrogen bonds with leucine 165 and alanine 167.39 Substitution of the leucine 165 by a serine should affect FGF binding. 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

JMEDGENET2013101603F2: Mapping of mutations L165S and L191S on crystal structure. Protein Data Bank structure 3OJV38 showing the extracellular Ig-like domains 2 and 3 of FGFR1 (amino acids 147–359) bound to FGF1 in surface representation, and detail around leucine 165 in ribbon representation. FGFR1 is shown in grey and FGF1 in blue. Leucines 165 and 191 are coloured in orange red. The detailed view is highlighting the interface between FGFR1 and FGF1 around leucine 165. Tyrosine 30 on FGF1 forms hydrogen bonds with leucine 165 and alanine 167.39 Substitution of the leucine 165 by a serine should affect FGF binding. These pictures were made using  UCSF Chimera.40
Mentions: In two of our patients with Hartsfield syndrome, we identified homozygous mutations affecting amino acid residues located in the extracellular ligand binding domain D2 of FGFR1: L165S, in patient 1, with a severe phenotype, and L191S, in patient 2, with a moderate phenotype (table 1, figure 1). Both parents of patient 1 were heterozygous for the L165S mutation, and were reported to be asymptomatic and spontaneously fertile. Parents of patient 2 were not available for testing. Mapping of these mutations on available FGFR1 structures from the RCSB Protein Data Bank shows that L165S is likely to affect FGF binding; the effect for L191S is less clear (figure 2). One previous KS patient has been described with a homozygous FGFR1 A167S mutation.20 This patient had KS, cleft palate, corpus callosum agenesis, vertebral anomalies, unilateral fusion of fourth and fifth metacarpal bones, and bilateral oligodactyly of feet (four digits).24

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