Abstract
BackgroundThe complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD.MethodsWe sequenced BMP2, 4 and 7 in 19 subjects with CPHD. For validation purposes, novel genetic variants were genotyped in 1046 healthy subjects. Additionally, potential functional relevance for most promising variants has been assessed by phylogenetic analyses and prediction of effects on protein structure.ResultsSequencing revealed two novel variants and confirmed 30 previously known polymorphisms and mutations in BMP2, 4 and 7. Although phylogenetic analyses indicated that these variants map within strongly conserved gene regions, there was no direct support for their impact on protein structure when applying predictive bioinformatics tools.ConclusionsA mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants. Further functional analyses are required to ultimately map the relevance of these novel variants in CPHD.
Highlights
The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors
The non-synonymous single nucleotide polymorphisms (SNPs) rs2273073, found to be heterozygous in one out of 19 analyzed subjects represents a T to G base pair exchange resulting in a serine to alanine amino acid substitution at protein position 37 (p.Ser37Ala)
An association of p.Arg190Ser substitution with the development of childhood IgA nephropathy has been described [29], the functional relevance cannot be predicted explicit based on SIFT and PolyPhen database search, it described as neutral or tolerated by MutPred and FATHMM but potentially disease associated by SNP&GO
Summary
The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. The development of the pituitary gland is a highly complex process, involving many signalling molecules and transcription factors [1,2,3]. Bone morphogenetic proteins (BMP) 2, 4 and 7 have a crucial role during the embryonic development of the pituitary gland [7]. The development of the pituitary gland is completed within the first trimester of pregnancy in humans [9]
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