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Link to original content: https://omim.org/entry/601538
Alternative titles; symbols
HGNC Approved Gene Symbol: PROP1
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38) : 5:177,992,235-177,996,242 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.3 | Pituitary hormone deficiency, combined, 2 | 262600 | Autosomal recessive | 3 |
PROP1 is a pituitary-specific paired-like homeodomain transcription factor that plays a crucial role in the proper development of somatotrophs, lactotrophs, thyrotrophs, and gonadotrophs (summary by Duquesnoy et al., 1998).
Duquesnoy et al. (1998) cloned a human PROP1 cDNA, which encodes a deduced 226-amino acid protein that shares 73% overall sequence identity with mouse Prop1.
PROP1 mRNA is expressed in the developing pituitary gland before PIT1 mRNA expression and maximum expression are observed at e12.0. After e14.5, PROP1 mRNA expression rapidly decreases, and only trace amounts of mRNA are detectable in adult mouse pituitary (Sornson et al., 1996). Nakamura et al. (1999) studied human PROP1 expression in adult pituitary and pituitary adenomas. Human PROP1 transcripts were detected in normal adult pituitary by Northern blot analysis, and in all pituitary adenomas examined by RT-PCR analysis.
Duquesnoy et al. (1998) determined that the PROP1 gene has at least 3 exons and spans less than 4 kb of genomic DNA.
There is considerable homology of synteny between mouse chromosome 11 and human 5q; the linkage of the df (Prop1) gene to the interleukin cluster (e.g., IL3, 147740) on chromosome 11 in the mouse suggested that the human PROP1 gene is located on human chromosome 5q. Rosenfeld and Wu (1998) confirmed that PROP1 is located on 5q by radiation hybrid mapping.
By fluorescence in situ hybridization, Duquesnoy et al. (1998) mapped the PROP1 gene to chromosome 5q35.
Inactivating mutations in PROP1 perturb ontogenesis of pituitary gonadotropes, somatotropes, lactotropes, and thyrotropes. These developmental defects result in deficiencies of luteinizing hormone (LH; 152780), follicle-stimulating hormone (FSH; 136530), growth hormone (GH; 139250), prolactin (PRL; 176760), and thyroid-stimulating hormone (TSH; 188540).
Wu et al. (1998) identified 4 families in which combined pituitary hormone deficiency (CPHD2; 262600) was produced by homozygosity or compound heterozygosity for inactivating mutations of the PROP1 gene. These mutations in the PROP1 gene resulted in a gene product with reduced DNA binding and transcriptional activation ability in comparison to the product of the murine df mutation (e.g., 601538.0002). In contrast to individuals with mutations in the human homolog of the mouse Pit1 gene, POU1F1 (173110), those with PROP1 mutations cannot produce luteinizing hormone or follicle-stimulating hormone at a sufficient level and do not enter puberty spontaneously. The results identified a major cause of combined pituitary hormone deficiency in humans and suggested a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes, and caudomedial thyrotropes.
In 5 affected individuals from 2 apparently unrelated consanguineous CPHD families, Fluck et al. (1998) identified homozygosity for the R120C mutation in the PROP1 gene (601538.0001).
Whereas a variety of PROP1 mutations have been reported, Cogan et al. (1998) found by analysis of 10 independent CPHD kindreds that the 301delAG allele (601538.0002) constitutes a major portion, perhaps 55%, of PROP1 mutant alleles. Cogan et al. (1998) also concluded from analysis of a tightly linked polymorphic marker that the 301delAG allele may be a recurring mutation.
In 2 individuals with CPHD2 (Hanhart dwarfism) from the isolated community on the Island of Krk in the Adriatic Sea, Krzisnik et al. (1999) identified homozygosity for a frameshift mutation in the PROP1 gene (601538.0014).
Nakamura et al. (1999) sequenced PROP1 cDNAs from pituitary adenomas. They found that the amino acid sequence of cloned human PROP1 cDNA was identical to the reported sequence, except for an ala142-to-thr substitution. They concluded that this substitution is a polymorphism because it did not alter transcriptional activity, and 7 of 28 (25%) alleles encoded ala. Because sequence analysis of PROP1 cDNAs from human pituitary adenomas only revealed 5 silent nucleic acid substitutions, Nakamura et al. (1999) concluded that PROP1 mutations do not represent a frequent mechanism of human pituitary tumorigenesis.
Deladoey et al. (1999) screened families and patients suffering from different forms of CPHD for PROP1 gene alterations to define possible hotspots and the frequency of the different gene alterations found. Of 73 subjects (36 families) analyzed, they identified 35 patients, belonging to 18 unrelated families, with CPHD caused by a PROP1 gene defect. The PROP1 gene alterations included 3 missense mutations, 2 frameshift mutations, and 1 splice site mutation. The 2 reported frameshift mutations could be caused by any 2-bp GA or AG deletion at either the 148-GGA-GGG-153 or 295-CGA-GAG-AGT-303 position. As any combination of a GA or AG deletion yields the same sequencing data, the authors called the frameshift mutations 149delGA and 296delGA, respectively. All but 1 mutation were located in the homeodomain of the PROP1 gene. Deladoey et al. (1999) concluded that 3 tandem repeats of the dinucleotides GA at location 296 to 302 in the PROP1 gene represent a hotspot for CPHD.
Vallette-Kasic et al. (2001) screened the PROP1 gene in 23 CPHD patients and identified homozygosity or compound heterozygosity for 4 mutations in 9 patients from 8 unrelated families. All mutations were located in exon 2 and affected only 2 different sites (see 601538.0005 and 601538.0009-601538.0011). Vallette-Kasic et al. (2001) stated that, in keeping with previous reports, they found no correlation between phenotype and genotype.
Reynaud et al. (2004) reported a homozygous R73C mutation of PROP1 (601538.0010) in all 10 patients studied from a large consanguineous Tunisian kindred with CPHD; heterozygosity for the mutation was found in 6 unaffected parents or sibs.
In a retrospective longitudinal analysis of 9 CPHD patients with known PROP1 mutations, primarily involving homozygous or compound heterozygous deletions (e.g., 601538.0002 and 601538.0008), Bottner et al. (2004) found that all patients developed at least partial adrenal insufficiency requiring hydrocortisone therapy. The authors concluded that anterior pituitary function in patients with PROP1 mutations deteriorates progressively and includes adrenal insufficiency as a feature of this condition, which has important clinical relevance in childhood and adolescence.
In 3 brothers from a consanguineous family of Tunisian descent with CPHD, who initially presented as cases of isolated hypogonadotropic hypogonadism, Reynaud et al. (2005) identified homozygosity for a nonsense mutation in the PROP1 gene (W194X; 601538.0013).
Osorio et al. (2002) stated that the pathogenesis of pituitary stalk interruption and ectopic posterior lobe, frequently observed on MRI in patients with GH deficiency (see 262400), was controversial. They performed pituitary stimulation tests and MRI, and studied the PROP1, GH1, and GHRHR (139191) genes, in 76 patients with GHD. Compared with the 62 patients without mutations, 14 patients with mutations had higher frequencies of consanguinity (P less than 0.001) and familial cases (P less than 0.05) and lower frequency of breech delivery or hypoxemia at birth (P less than 0.005). On MRI, all patients with mutations had an intact pituitary stalk, whereas it was interrupted or thin in 74% without mutations (P less than 0.001). The posterior pituitary lobe was in normal position in 92% of patients with mutations versus 13% without mutations (P less than 0.001). Among patients with combined pituitary hormone deficiency, hormonal deficiencies were of pituitary origin in all with PROP1 and PIT1 mutations and suggestive of hypothalamic origin in 81% without mutations. PROP1, GH1, and GHRHR mutations were associated with consanguineous parents, intact pituitary stalk, normal posterior lobe, and pituitary origin of hormonal deficiencies. Osorio et al. (2002) concluded that pituitary MRI and hormonal response to stimulation tests are useful in selection of patients and candidate genes to elucidate the etiologic diagnosis of GHD.
The Snell dwarf mouse (dw) has a mutation in the Pit1 gene (POU1F1; 173110) which encodes pituitary-specific transcription factor-1. Mutations in the human homolog, PIT1, are the basis of combined pituitary hormone deficiency in humans (e.g., 173110.0001). Reasoning that the Snell dwarf might represent a point mutation, Li et al. (1990) did studies which demonstrated a G-to-T change that converted the tryptophan residue in the POU-homeodomain (trp261) to cysteine. Neither mRNA nor protein was detected in either of the 2 types of dwarf mice. They also demonstrated that the Ames dwarf mouse (df) has a nonallelic mutation that maps to mouse chromosome 11 and is associated with absence of detectable Pit1 gene expression. Thus, the Ames mutation df appeared to be epistatic to the Pit1 locus. The df locus may be involved in the regulation of Pit1, or perhaps in conjunction with Pit1, in the specification and/or maintenance of the 3 specific pituitary cell types affected by the mutation. Andersen et al. (1995) pointed out that the Ames dwarf exhibits a phenotype identical to that of the Pit1-mutated mice. Their studies indicated that initial activation of the Pit1 gene is deficient in the Ames dwarf. This suggested that the df gene is required for activation of the Pit1 gene.
Sornson et al. (1996) isolated the murine gene that is mutant in the Ames dwarf (df) by positional cloning and identified a tissue-specific, 'paired'-like homeodomain transcription factor, which they termed 'Prophet of Pit1' (Prop1). The df phenotype resulted from an apparent failure of initial determination of the Pit1 lineage required for production of growth hormone, prolactin, or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit1 gene expression. The results suggested to Sornson et al. (1996) that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis.
Analysis of double heterozygotes and double mutants by Gage et al. (1996) indicated that the df and dw genes act sequentially in the same genetic pathway. Double heterozygotes had no reduction in growth rate or final adult size. Double homozygotes had essentially the same phenotype as the single mutants and were recovered at the predicted frequency, indicating that there are no previously unrecognized, redundant functions of the 2 genes. The df mutants failed to extinguish expression of the homeobox gene Rpx on embryonic day 13.5 (e13.5), and the size of their nascent pituitary glands was reduced by e14.5, while Pit1dw mutants downregulate Rpx appropriately and exhibit normal cell proliferation up to e14.5. These occurrences suggest that df acts earlier in the differentiation pathway than Pit1 to regulate pituitary ontogeny.
Brown-Borg et al. (1996) noted that Ames dwarf mice (df/df) are of normal body size at birth but postnatal growth is severely retarded and the body size of adult animals is approximately one-third of normal. The authors found, however, that df/df mice lived much longer than normal mice, with a difference in average life span being more than 350 days for males and more than 470 days for females. Two df/df females reached the remarkable age of 4 years. These findings were particularly striking because Ames dwarfs exhibit some characteristics of reduced immune function and the animals were maintained in a conventional environment and fed lab chow and tap water without restriction. Brown-Borg et al. (1996) speculated on the mechanism of the increased survival.
Cushman et al. (2001) generated transgenic mice which constitutively expressed Prop1. The terminal differentiation of pituitary gonadotropes was delayed, resulting in transient hypogonadism and a delay in the onset of puberty. Thyrotrope differentiation occurred normally, but thyrotrope function was impaired, resulting in mild hypothyroidism. Aged mice exhibited defects consistent with misregulation of pituitary cell proliferation, including adenomatous hyperplasia with the formation of Rathke cleft cysts and tumors. The authors concluded that silencing Prop1 is important for normal pituitary development and function, and that gain-of-function mutations in PROP1 could contribute to common human pituitary endocrinopathies and tumors.
By reducing the number of calories consumed by Ames dwarf mice, Bartke et al. (2001) investigated whether the longevity associated with Ames dwarf mice is influenced by similar or independent mechanisms to the longevity associated with caloric restrictions. Bartke et al. (2001) found that 70% caloric restriction conferred a further life span increase in the dwarf, indicating that the 2 factors may act through different pathways. Survival plots indicated that although both dwarfism and calorie restriction extend longevity, the effect of reduced food intake is associated primarily with a change in the slope of the survival curve (i.e., it reduces the rate of age-related mortality), whereas the effect of dwarfism mainly reflects a shift in the age at which the age-dependent increase in mortality risk first becomes appreciable. Calorie restriction, therefore, seems to decelerate aging, whereas the Prop1(df) allele seems to delay it.
Nasonkin et al. (2004) showed that deletion of Prop1 in mice caused severe pituitary hypoplasia with failure of the entire Pit1 lineage and delayed gonadotrope development. Pituitary hormone deficiencies caused secondary endocrine problems and a high rate of perinatal mortality due to respiratory distress. Lung atelectasis in mutants correlated with reduced levels of NKX2.1 (TITF1; 600635) and surfactant (SFTPA1; 178630). Lethality of mice homozygous for either the null allele or a spontaneous hypomorphic allele was strongly influenced by genetic background.
The mouse gene Prop1, which is mutant in the Ames dwarf (df), was isolated by Sornson et al. (1996). The first humans with CPHD due to PROP1 defects were reported by Wu et al. (1998). The human PROP1 mutations resulted in a gene product with reduced DNA-binding and transcriptional activation ability in comparison to the product of the Ames dwarf mutation (e.g., 601538.0002).
In a family with 2 brothers and a sister with combined pituitary hormone deficiency (CPHD2; 262600), Wu et al. (1998) identified a C-to-T transition resulting in an arg120-to-cys amino acid substitution.
In 5 affected individuals from 2 apparently unrelated consanguineous CPHD families, Fluck et al. (1998) identified homozygosity for the R120C mutation in the PROP1 gene. The authors noted that there was variability in the phenotype, even among these patients with the same mutation.
In each of 2 separate families, Wu et al. (1998) showed that 3 sibs with combined pituitary hormone deficiency (CPHD2; 262600) carried a 2-bp deletion (301A and 302G) leading to a frameshift in the coding sequence starting at codon 101 and premature termination at codon 109. The truncation resulted in the loss of the DNA-binding homeodomain and the C-terminal transactivation domain of PROP1.
Cogan et al. (1998) determined the frequency of the 301delAG mutation in exon 2 of PROP1 in 10 independently ascertained combined pituitary hormone deficiency (CPHD) kindreds and 21 sporadic cases of CPHD from 8 different countries. They found that 55% (11 of 20) of the PROP1 alleles were 301delAG in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles in the 21 sporadic cases were 301delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given thyrotropin-releasing hormone stimulation tests) was 50% (3 of 6) in the CPHD cases with pituitary defects, and 0% (0 of 34) in the CPHD cases with hypothalamic defects. Using whole genome radiation hybrid analysis, they localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. The authors concluded that analysis of this marker in affected subjects with the 301delAG mutation suggests that rather than being inherited from a common founder, 301delAG may be a recurring mutation.
In 2 unrelated females with CPHD, Mendonca et al. (1999) identified homozygosity for the 301AG deletion in the PROP1 gene. MRI findings changed over time in these patients, and 1 had partial cortisol deficiency. The authors concluded that a large sella turcica and an enlarged pituitary anterior lobe with hyperintense enhanced T1 signal on MRI suggests PROP1 deficiency; that pituitary morphology can change during follow-up of patients with PROP1 mutations; and that hormonal deficiencies associated with PROP1 mutations can include the adrenal axis.
In 10 CPHD patients from a large Brazilian kindred, 9 of whom were born of consanguineous marriages, Pernasetti et al. (2000) identified homozygosity for the 301AG deletion in PROP1. The authors observed ACTH/cortisol insufficiency in 5 of 6 of the older patients and in one 11-year-old patient, and suggested that the phenotype of this mutation includes late-onset adrenal insufficiency.
Riepe et al. (2001) found this mutation in compound heterozygosity with 150delA (601538.0008) in 2 brothers with typical manifestations of PROP1 deficiency.
The 301-302delAG frameshift mutation was found in homozygous state as the cause of the CPHD in the Hutterite cases reported by McKusick and Rimoin (1967) (Mosely et al., 2002).
In 3 adult sibs, aged 18 to 25 years, with short stature, hypothyroidism, and lack of pubertal maturation, Lee et al. (2004) identified homozygosity for the 301AG deletion in PROP1. All 3 patients responded with a dramatic increase in linear growth to treatment with GH and thyroid replacement administered prior to beginning sex steroid replacement therapy.
In a sporadic case of combined pituitary hormone deficiency (CPHD2; 262600), Wu et al. (1998) identified compound heterozygosity for mutations in the PROP1 gene. A 2-bp deletion (301delAG; 601538.0002) was inherited from the mother; the paternal allele carried a T-to-A transversion at nucleotide 349, resulting in a phe117-to-ile amino acid substitution. Magnetic resonance imaging revealed hypocellular pituitary in this patient. This patient and the affected individuals homozygous for the 301delAG deletion failed to respond to growth hormone-releasing hormone (GHRH; 139190), thyrotropin-releasing hormone (TRH; 613879), and LH-releasing hormone (LHRH; 152760) stimulation.
In 5 Russian children with combined pituitary hormone deficiency (CPHD2; 262600), including a brother and sister and 3 unrelated children, Fofanova et al. (1998) identified compound heterozygosity for 2 2-bp deletions in the PROP1 gene, 149delGA and 296delGA (601538.0005), both of which result in premature termination of the protein due to a stop codon at residue 109. Another affected brother and sister and an unrelated girl with CPHD were homozygous for 149delGA. All parents were of normal stature and each was heterozygous for a wildtype allele and 1 of the deletions, respectively.
For discussion of the 2-bp deletion in the PROP1 gene (296delGA) that was found in compound heterozygous state in patients with combined pituitary hormone deficiency (CPHD2; 262600) by Fofanova et al. (1998), see 601538.0004.
In 8 patients from a large Dominican kindred with CPHD2, the largest such family reported to that time, Rosenbloom et al. (1999) identified homozygosity for the 296delGA mutation in the PROP1 gene.
Deladoey et al. (1999) found this mutation in patients from distinct genetic backgrounds and described the site of the mutation as one of high mutability.
Vallette-Kasic et al. (2001) found this mutation in homozygosity in 5 patients with combined pituitary hormone deficiency from 4 distinct families.
Osorio et al. (2000) studied a Brazilian girl, offspring of first cousins, who presented with short stature and combined pituitary hormone deficiency (CPHD2; 262600). Her cortisol response to hypoglycemia was determined at age 4.9, 10.7, and 14.1 years and remained normal. Magnetic resonance imaging at the age of 9 years revealed an anterior pituitary lobe of diminished height (3 mm; normal, 4.5 +/- 0.6), but radiography revealed a sella turcica volume above the normal mean. Sequencing of the PROP1 gene revealed homozygosity for a T-to-C transition at nucleotide 263 of the PROP1 gene, resulting in replacement of a highly conserved phenylalanine at codon 88 by serine (F88S). F88 constitutes the hydrophobic core of the first helix of the homeodomain of PROP1, and the substitution by the polar residue serine was expected to alter the secondary structure and impair binding of the mutated PROP1 to DNA target sequences. Osorio et al. (2000) introduced the F88S mutation (which corresponds to murine F85S) into the murine Prop1 cDNA and assessed its consequences on DNA binding and trans-activation in vitro. In contrast to wildtype Prop1, the F88S mutant showed no significant DNA binding to a Prop1 response element in gel shift assays. Transcriptional activation of a luciferase reporter gene was reduced to approximately 34% compared with that of wildtype Prop1 in transiently transfected human embryonic kidney cells.
Agarwal et al. (2000) analyzed the PROP1 gene in a large consanguineous Indian pedigree with combined pituitary hormone deficiency (CPHD2; 262600) and identified homozygosity for a 13-bp deletion in affected individuals, predicted to generate a null allele. Severe cortisol deficiency was observed in 2 patients in this family, suggesting a role for PROP1 in the differentiation and/or maintenance of corticotroph cells in the mature anterior pituitary.
In 2 brothers with combined pituitary hormone deficiency involving GH, TSH, PRL, and gonadotropins (CPHD2; 262600), who later also developed deficiencies of ACTH and cortisol secretion, Riepe et al. (2001) identified compound heterozygosity for a 1-bp deletion (150delA) in the PROP1 gene and a 2-bp deletion (301delAG; 601538.0002). Both patients showed early pituitary enlargement by MRI, followed by subsequent marked hypoplasia.
In a French patient with combined pituitary hormone deficiency (CPHD2; 262600), Vallette-Kasic et al. (2001) found a novel mutation in PROP1, an arg73-to-his (R73H) substitution, resulting from a G-to-A transition at nucleotide 218 of the PROP1 gene.
In 2 brothers from a consanguineous Tunisian family with combined pituitary hormone deficiency (CPHD2; 262600), Duquesnoy et al. (1998) identified a 217C-T transition in exon 2 of the PROP1 gene, resulting in an arg73-to-cys (R73C) substitution. The authors noted that arginine-73 is conserved in 95% of the more than 400 known homeodomain proteins.
Vallette-Kasic et al. (2001) found the R73C mutation in homozygosity in 2 patients from 2 unrelated families, and in compound heterozygosity with R99X (601538.0011) in 1 patient.
Reynaud et al. (2004) found this mutation in homozygosity on all affected members of a large consanguineous Tunisian kindred. Transfection studies demonstrated that the mutant protein had 11.5% of the transactivation capacity of the wildtype protein. No detectable DNA binding was observed with R73C in electromobility shift assays, whereas in vitro translated PROP1 and R73C proteins were similar in their expression and electrophoretic properties.
Vallette-Kasic et al. (2001) found a C-to-T transition at nucleotide 295 of the PROP1 gene, resulting in substitution of arginine with a stop codon at codon 99 (R99X), in compound heterozygosity with R73C (601538.0010) in 1 patient with combined pituitary hormone deficiency (CPHD2; 262600).
In 2 sibs, born to consanguineous parents, with combined pituitary hormone deficiency (CPHD2; 262600) who presented with short stature, Vieira et al. (2003) detected a novel homozygous transition 296G-A in exon 2 of the PROP1 gene that caused substitution of a highly conserved arginine by a glutamine at codon 99 (R99Q) in the second helix of the DNA-binding domain of the PROP1 protein. The index patient, a boy, was initially diagnosed with constitutional growth delay based on familial short stature, low parental target height, normal GH secretion, and imaging of the pituitary gland. On follow-up, auxologic data and pubertal delay prompted a thorough reevaluation, which documented GH, TSH, and gonadotropin deficiencies. Compared with wildtype PROP1, R99Q displays a significant decrease in DNA binding on a paired box response element (PRDQ9) and transactivation of a luciferase reporter gene.
In 3 brothers from a consanguineous family of Tunisian descent with CPHD, who initially presented as cases of isolated hypogonadotropic hypogonadism (CPHD2; 262600), Reynaud et al. (2005) identified homozygosity for a 582G-A transition in the PROP1 gene, resulting in a trp194-to-ter (W194X) substitution that was predicted to truncate the protein in its transactivation domain. Transfection studies confirmed the deleterious effect of this mutation, whose transactivation capacity was only 34.4% that of wildtype. Unexpectedly altered DNA-binding properties suggested that the C-terminal end of the factor plays a role in protein-DNA interaction.
In 2 individuals with Hanhart dwarfism (CPHD2; 262600) from the isolated community on the Island of Krk, Krzisnik et al. (1999) identified homozygosity for a 1-bp deletion (A) in codon 50 in exon 2 of the PROP1 gene, resulting in a frameshift and premature termination at codon 164. The predicted protein lacks all 3 alpha helices in the paired DNA-binding domain as well as the C-terminal transcriptional activation domain.
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