Peptide hormones such as parathyroid hormone (PTH) are

processed after translation through steps that are critical for their proper folding, secretion and activity. This mini-review will briefly summarize the known mutations of the preproparathyroid hormone gene that are known to interfere with proper processing of PTH and are a cause of primary hypoparathyroidis

Schipani, Ernestina

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Ernestina SchipaniEndocrine Unit, MGH-Harvard Medical School, Boston, MA,USAAddress for correspondence: Ernestina Schipani, M.D.Massachusetts General Hospital, Endocrine Unit, 50 Blossom StreetWellman 501, Boston, MA 02114-2696, USAPh. +1 617 726 3966Fax +1 617 726 7543E-mail: schipani@helix.mgh.harvard.eduSummaryPeptide hormones such as parathyroid hormone (PTH) areprocessed after translation through steps that are critical fortheir proper folding, secretion and activity. This mini-reviewwill briefly summarize the known mutations of the pre-proparathyroid hormone gene that  are known to interfere withproper processing of PTH and are a cause of primary hy-poparathyroidism. KEY WORDS: PTH, hypoparathyroidism.Parathyroid hormone (PTH), one of the major regulators of cal-cium and phosphate homeostasis, is synthesized by theparathyroid glands as a larger precursor, pre-proparathyroidhormone (preproPTH) (1). The preproPTH is first cleaved toproPTH and then to PTH. The preproPTH has 25-residue “pre”or signal sequence and a 6-residue “pro” sequence. The signalsequence, along with the short “pro” sequence, has the func-tion to direct the protein into the secretory pathway. Duringtransit across the membrane of the endoplasmic reticulum, thesignal sequence is cleaved off and rapidly degraded. Like mostother signal sequences found at the beginning of precursors ofsecreted proteins, the signal sequence of preproPTH containsan interrupted stretch of hydrophobic and non-polar aminoacids. The importance of the signal sequence for normal secre-tion of PTH is illustrated by the hypoparathyroidism inherited infamilies carrying mutations in the signal sequence of pre-proPTH (see below). Conversely, the role of the short “pro” se-quence is not completely understood; however, experimentalevidence strongly suggest that the prohormonal hexapeptidesequence of preproPTH functions to optimize the efficiencyand accuracy of signal-sequence cleavage (2). After cleavageof the “pro” sequence, the mature PTH 1-84 is accumulatedand stored into secretory granules. Idiopathic hypoparathyroidism is a heterogenous group ofmetabolic disorders characterized by hypocalcaemia and hy-pophosphatemia due to deficient secretion of PTH, and notsecondary to surgery or other acquired disorders (3). Idiopathichypoparathyroidism can be either familial or sporadic. Sporadicidiopathic hypoparathyroidism is more frequent. Familial idio-pathic hypoparathyroidism can be part of a complex autoim-mune disorder or occur as an isolated entity. This form of thedisorder is called “familial isolated hypoparathyroidism” (FIH)(3). This review will briefly discuss the cases of FIH due to mu-tations in the preproPTH sequence. The human PTH gene contains 3 exons that are located on theshort arm of chromosome 11 (4). Exon 1 contains the untrans-lated region. Exon 2 encodes the signal peptide and part of theprohormone sequence. Exon 3 encodes the rest of the prohor-mone sequence, the 84-aminoacid peptide, and the 3’-untrans-lated region (4). The first indication that the preproPTH sequence could be as-sociated to FIH was a study by Ahn and colleagues in which in2 out of 8 families with FIH concordance was identified be-tween the inheritance of hypoparathyroidism and specific PTHalleles in affected members. In particular, in one family, forwhich inheritance of FIH was consistent with the presence ofhypoparathyroidism, evidence for linkage analysis was suffi-ciently strong (LOD score 1.505) (3). Arnold and colleaguespursued this interesting finding, and they cloned and analyzedthe putatively abnormal preproPTH gene and the putative wild-type allele from an affected member of this last family (5). Asingle point mutation (T to C transition) in exon2 that resultedin substitution of cysteine with an arginine at position 18 of thesignal sequence was identified in the putatively abnormal gene,and not in the normal one (Figure 1). The presence of this sin-gle point mutation was confirmed in affected family membersand excluded in the others. Detailed and elegant analysis ofthe biological consequences of this missense mutation byKaraplis and colleagues provided clear evidence that the muta-tion was associated with deleterious effects on the processingf preproPTH to proPTH (6). Thakker and colleagues investigated one kindred with autoso-mal recessive FIH, and identified a G to C substitution in thefirst nucleotide of intron 2 of the PTH gene, generating a donorsplice mutation (7). This study revealed that the patients werehomozygous for the mutant alleles, while the unaffected rela-tiv s were heterozygous, and unrelated normals were homozy-gous for the wild type alleles. The mutation resulted in exonskipping with a loss of exon 2, which encodes the initiationcodon and the signal peptide, thereby causing PTH deficiency(7).In 1999, a novel mutation of the signal peptide of the pre-proPTH gene associated with autosomal recessive FIH wasdescribed (8). A replacement of T to C was found in the firstnucleotide of position 23 in the 25-amino acid signal peptide(Figure 1). This resulted in the replacement of the normal ser-in  with a proline. Affected family members were homozygousfor the mutation, whereas the parents were heterozygous, sup-porting autosomal recessive inheritance. As this mutation isvery close to the cleavage site, it is likely that the preproPTHmutant may not be cleaved by signal peptidase at the normalposition, and it might be degraded in rough endoplasmic reticu-lum. Taken together, mutations in the PTH gene have been report-ed in three families with FIH. The first family had mutation inthe hydrophobic core of the signal peptide, producing the auto-s mal dominant form of FIH. The second family had a mutationn the exon2-intron2 junction that skipped the next exon andClinical Cases in Mineral and Bone Metabolism 2004; 1(2): 107-108 107Mutations of preproparathyroid hormone gene in primary hypoparathyroidismMini-reviewFOR REVIEW ONLY© CIC EDIZIONI INTERNAZIONALIproduced the autosomal recessive form of FIH. The third familyhad a new autosomal recessive form of FIH with a point muta-tion in the signal peptide that leads to the amino acid substitu-tion serine 23 to proline at position.Further studies are now required to elucidate whether genescoding for other molecules, such as calcium sensing receptorare indeed involved in additional cases of FIH for which the ge-netic defect has not been yet identified (9).References1. Wiren KM, Freeman MW, Potts JT, Jr., Kronenberg HM. Pre-proparathyroid hormone. A model for analyzing the secretory path-way. Ann N Y Acad Sci. 1987;493:43-9.2. Wiren KM, Potts JT, Jr, Kronenberg HM. Importance of the propep-tide sequence of human preproparthyroid hormone for signal se-quence function. J Biol Chem. 1988;263:19771-19777.3. Ahn TG, Antonarakis SE, Kronenberg HM, Igarashi T, Levine MA.Familial isolated hypoparathyroidism: a molecular genetic analysisof 8 families with 23 affected persons. Medicine (Baltimore). 1986;65(2):73-81.4. Kronenberg HM, Bringhurst FR, Nussbaum S, Jüppner H, Abou-Samra AB, Segre GV, Potts JT, Jr. Parathyroid hormone: Biosyn-thesis, secretion, chemistry, and action. In: Mundy GR, Martin TJ,editors. Handbook of Experimental Pharmacology: Physiology andPharmacology of Bone. Heidelberg, Germany: Springer-Verlag;1993. p. 185-201.5. Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, KronenbergHM. Mutation of the signal peptide-encoding region of the pre-proparathyroid hormone gene in familial isolated hypoparathy-roidism. J Clin Invest. 1990;86(4):1084-7.6. Karaplis AC, Lim SK, Baba H, Arnold A, Kronenberg HM. Inefficientmembrane targeting, translocation, and proteolytic processing bysignal peptidase of a mutant preproparathyroid hormone protein. JBiol Chem. 1995;270(4):1629-35.7. Parkinson DB, Thakker RV. A donor splice site mutation in theparathyroid hormone gene is associated with autosomal recessivehypoparathyroidism. Nat Genet. 1992;1(2):149-52.8. Sunthornthepvarakul T, Churesigaew S, Ngowngarmratana S. Anovel mutation of the signal peptide of the preproparathyroid hor-mone gene associated with autosomal recessive familial isolatedhypoparathyroidism. J Clin Endocrinol Metab. 1999;84(10):3792-6.9. Yamamoto T, Yoshimasa Y, Koshiyama H, Sugiyama K, Okigaki M,Yamada T, Ishii H, Yagura T, Fujimoto K, Ohnishi T, Koh T, Hino M,Kurahachi H, Yoshimasa T, Nakao K. 1997 Lack of mutations ofpreproparathyroid hormone gene in three kindreds with familial iso-lated hypoparathyroidism. Endocr J. 1997;44(1):175-80.108 Clinical Cases in Mineral and Bone Metabolism 2004; 1(2): 107-108E. SchipaniFigure 1 - Human signal sequence and “pro” sequence of human pre-proPTH.Missense mutations identified inFIH are shown.FOR REVIEW ONLY© CIC EDIZIONI INTERNAZIONALI

Mutations of preproparathyroid hormone gene 

in primary hypoparathyroidism

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Mutations of preproparathyroid hormone gene in primary hypoparathyroidism

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