Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia

P Q Thomas, M T Dattani, J M Brickman, D McNay, G Warne, M Zacharin, F Cameron, J Hurst, K Woods, D Dunger, R Stanhope, S Forrest, I C Robinson, R S Beddington

Research output: Contribution to journalArticle

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Abstract

We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse. However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of HESX1 mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the Hesx1 null allele show a milder SOD phenocopy, implying that heterozygous mutations in human HESX1 could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the HESX1-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the HESX1 locus, indicated that only one HESX1 mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the HESX1 gene.
Original languageEnglish
Pages (from-to)39-45
Number of pages7
JournalHuman Molecular Genetics
Volume10
Issue number1
Publication statusPublished - 2001

Fingerprint

Septo-Optic Dysplasia
Mutation
Hypopituitarism
Alleles
Pituitary Dwarfism
Penetrance
Homeobox Genes
Electrophoretic Mobility Shift Assay
Missense Mutation
Mutant Proteins
Optic Nerve
Haplotypes
Phenotype

Keywords

  • Alleles
  • Basic Helix-Loop-Helix Transcription Factors
  • Child
  • Chromosomes, Artificial, Yeast
  • DNA
  • Family Health
  • Female
  • Haplotypes
  • Heterozygote
  • Homeodomain Proteins
  • Humans
  • Infant
  • Male
  • Mutation
  • Mutation, Missense
  • Optic Nerve
  • Pedigree
  • Phenotype
  • Pituitary Gland
  • Repressor Proteins

Cite this

Thomas, P. Q., Dattani, M. T., Brickman, J. M., McNay, D., Warne, G., Zacharin, M., ... Beddington, R. S. (2001). Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Human Molecular Genetics, 10(1), 39-45.

Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. / Thomas, P Q; Dattani, M T; Brickman, J M; McNay, D; Warne, G; Zacharin, M; Cameron, F; Hurst, J; Woods, K; Dunger, D; Stanhope, R; Forrest, S; Robinson, I C; Beddington, R S.

In: Human Molecular Genetics, Vol. 10, No. 1, 2001, p. 39-45.

Research output: Contribution to journalArticle

Thomas, PQ, Dattani, MT, Brickman, JM, McNay, D, Warne, G, Zacharin, M, Cameron, F, Hurst, J, Woods, K, Dunger, D, Stanhope, R, Forrest, S, Robinson, IC & Beddington, RS 2001, 'Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia' Human Molecular Genetics, vol. 10, no. 1, pp. 39-45.
Thomas PQ, Dattani MT, Brickman JM, McNay D, Warne G, Zacharin M et al. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Human Molecular Genetics. 2001;10(1):39-45.
Thomas, P Q ; Dattani, M T ; Brickman, J M ; McNay, D ; Warne, G ; Zacharin, M ; Cameron, F ; Hurst, J ; Woods, K ; Dunger, D ; Stanhope, R ; Forrest, S ; Robinson, I C ; Beddington, R S. / Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. In: Human Molecular Genetics. 2001 ; Vol. 10, No. 1. pp. 39-45.
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abstract = "We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse. However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of HESX1 mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the Hesx1 null allele show a milder SOD phenocopy, implying that heterozygous mutations in human HESX1 could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the HESX1-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the HESX1 locus, indicated that only one HESX1 mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the HESX1 gene.",
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T1 - Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia

AU - Thomas, P Q

AU - Dattani, M T

AU - Brickman, J M

AU - McNay, D

AU - Warne, G

AU - Zacharin, M

AU - Cameron, F

AU - Hurst, J

AU - Woods, K

AU - Dunger, D

AU - Stanhope, R

AU - Forrest, S

AU - Robinson, I C

AU - Beddington, R S

PY - 2001

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N2 - We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse. However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of HESX1 mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the Hesx1 null allele show a milder SOD phenocopy, implying that heterozygous mutations in human HESX1 could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the HESX1-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the HESX1 locus, indicated that only one HESX1 mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the HESX1 gene.

AB - We have previously shown that familial septo-optic dysplasia (SOD), a syndromic form of congenital hypopituitarism involving optic nerve hypoplasia and agenesis of midline brain structures, is associated with homozygosity for an inactivating mutation in the homeobox gene HESX1/Hesx1 in man and mouse. However, as most SOD/congenital hypopituitarism occurs sporadically, the possible contribution of HESX1 mutations to the aetiology of these cases is presently unclear. Interestingly, a small proportion of mice heterozygous for the Hesx1 null allele show a milder SOD phenocopy, implying that heterozygous mutations in human HESX1 could underlie some cases of congenital pituitary hypoplasia with or without midline defects. Accordingly, we have now scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism. Three different heterozygous missense mutations were detected in individuals with relatively mild pituitary hypoplasia or SOD, which display incomplete penetrance and variable phenotype amongst heterozygous family members. Gel shift analysis of the HESX1-S170L mutant protein, which is encoded by the C509T mutated allele, indicated that a significant reduction in relative DNA binding activity results from this mutation. Segregation analysis of a haplotype spanning 6.1 cM, which contains the HESX1 locus, indicated that only one HESX1 mutation was present in the families containing the C509T and A541G mutations. These results demonstrate that some sporadic cases of the more common mild forms of pituitary hypoplasia have a genetic basis, resulting from heterozygous mutation of the HESX1 gene.

KW - Alleles

KW - Basic Helix-Loop-Helix Transcription Factors

KW - Child

KW - Chromosomes, Artificial, Yeast

KW - DNA

KW - Family Health

KW - Female

KW - Haplotypes

KW - Heterozygote

KW - Homeodomain Proteins

KW - Humans

KW - Infant

KW - Male

KW - Mutation

KW - Mutation, Missense

KW - Optic Nerve

KW - Pedigree

KW - Phenotype

KW - Pituitary Gland

KW - Repressor Proteins

M3 - Article

VL - 10

SP - 39

EP - 45

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 1

ER -