Eleven DNA sequence polymorphisms (Table IV) with allele fre­quencies ranging from 1% to 25% have also been reported. Only one of these polymorphisms is located within the coding region and this is a third base C to T transition involving nucleotide 33 of codon 11 (TAC—TAT) which does not alter the naturally oc­curring tyrosine residue. None of the polymorphisms is in the vicin­ity of donor or acceptor splice sites, and an analysis of the altered sequences does not predict splicing abnormalities. The recogni­tion of these polymorphisms, together with their allele frequencies, is important as this will help prevent ambiguities in establishing a genetic diagnosis for patients with HPT-JT and FIHP.

Screening in HPT-JT and HRPT2 mutational analysis

The size of the HRPT2 gene, the absence of a genotype-phe- notype correlation together with an absence of a ‘mutational hotspot’ make the implementation of mutational analysis in a diagnostic and clinical setting arduous, time-consuming and expensive. Nevertheless, diagnostic DNA testing for HRPT2 mutations should be considered in patients with HPT-JT, FIHP and ‘non-familial’ parathyroid carcinomas, as it is likely to help in their clinical management and in the genetic counselling and screening of their relatives. The genetic counselling and screening should be extended to include second-degree rela­tives as non-penetrance can be >30%. The parathyroid, uterine and renal pathologies that occur in HPT-JT patients in­dicate that screening for such tumours is likely to result in an earlier detection and hence intervention that will help to reduce morbidity and mortality. Guidelines (Table V) for regular screening for the development of HPT-JT associated tumours have recently been published, although these suggested guidelines will need to be modified in the light of new clinical and genetic data. Mutational analysis of the HRPT2 gene is available, e.g. from the Department of Clinical Genetics, Churchill Hospital, Oxford, OX3 7LJ, UK.

Table IV – HRPT2 polymorphisms and their frequencies.

Location (nt)a

Sequence

Chromosomesc

Allele

Ref. #e

changeb

frequencies

5′ of ATG (-11)

ga

54

0.98 / 0.02

29

Exon 1 (33)

CT

121

0.99 / 0.01

6

Intron 2 (+28)

c—>t

171

0.70 / 0.30

6, 29

Intron 2 (+28 to +31)

del ccta

175

0.95 / 0.05

6, 29

Intron 7 (+33)

d(ga)8

121

0.96 / 0.04

6

Intron 7 (+50)

del ag

56

0.98 / 0.02

29

Intron 12 (+8)

t c

56

0.98 / 0.02

29

Intron 12 (-86)

c t

121

0.95 / 0.05

6

Intron 12 (-109)

t g

121

0.91 / 0.09

6

Intron 13 (+20)

a c

121

0.99 / 0.01

6

Intron 15 (-17)

c g

80

0.93 / 0.07

29

Function of HRPT2 and PARAFIBROMIN

The role of the HRPT2 gene and its encoded protein, PARAFI­BROMIN, in normal cellular function and the mechanisms by which its abnormalities lead to tumours of the HPT-JT syn­drome, remain to be elucidated. PARAFIBROMIN has been shown to be a nuclear protein. Moreover, the ~200 amino acids of the C-terminal segment of PARAFIBROMIN have 27% sequence identity with the yeast protein Cdc73, which is a component of the yeast Paf1 complex that interacts with RNA polymerase II. Furthermore, recent studies have shown that the human homologues of the yeast Paf1 complex are associated with PARAFIBROMIN. Thus, as part of this protein complex, PARAFIBROMIN may regulate post-tran- scriptional events and histone modification and thereby regulate cell proliferation.
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Table V – HPT-JT suggested guidelines for screening patients; asymptomatic mutation carriers; and first- and second-degree relatives in families without identified germline HRPT2 mutations.

Tumoura

Testb

Frequencyc

Parathyroid

Serum Ca2+, PTH

6 to 12 monthly

Ossifying jaw fibromas

Panoramic jaw X-rays with neck shieldingd

5 yearly

Renal

Abdominal MRIde

5 yearly

Uterine

Ultrasound (transvaginal or transabdominal), and additional imaging
± D&C if indicated’

Annually