Genetics and Genomics in Endocrinology

Transcription

1 Genetics and Genomics in Endocrinology Dr. Peter Igaz MD MSc PhD 2 nd Department of Medicine Faculty of Medicine Semmelweis University

2 Genetics-based endocrine diseases I. Monogenic diseases: Multiple endocrine neoplasia (1, 2) Von Hippel-Lindau disease Congenital adrenal hyperplasia (21-hydroxylase, 17a-hydroxylase, 3b-hydroxysteroid dehydrogenase, 11b-hydroxylase, STAR-defect) Glucocorticoid remediable hyperaldosteronism. Chromosome aberrations: e.g. Turner-syndrome, Prader-Willi-syndrome, Klinefelter-syndrome

3 Genetics-based endocrine diseases II. Rare diseases: Li-Fraumeni-syndrome, Beckwith- Wiedemann-syndrome, Carney-complex, McCune-Albright syndrome, DAX1 mutation, succinate-dehydrogenase mutation stb. Polymorphisms (SNP) MHC-haplotype association Pl. diabetes mellitus, 21-hydroxylase. Poliggenic diseases Pl. diabetes mellitus, hypertension. Genomics

4 Major forms of mutations Germline Present in all cells, can be identified from peripheral blood: e.g. RET, menin, VHL, CYP21 (McCune- Albright syndrome) Somatic Only in certain tissues, Mainly tumours, de novo mutations: e.g. RET-PTC. Major forms of point mutations Missense: aminoacid replacement Nonsense: STOP codon leading to premature termination Frameshift: faulty amino acid sequence

5 MEN1-syndrome Inheritance: autosomal dominant or sporadic. Responsible gene: MEN1 gene, product menin, tumor suppressor gene. 10 exons More than 400 known inactivating mutations, most of them nonsense or frameshift mutations leading to major disturbances of protein function. No mutation hotspots. No unambiguous genotype-phenotype correlations. No mutation found in % of clinically proven MEN1 cases.

6 MEN2 syndrome Inheritance: autosomal dominant inherited or sporadic. MEN2A, MEN2B, FMTC RET (Rearranged during Transfection) protooncogene - activating mutations. 21 exons Mutation hotspots (exons 11 and 10) Most frequently affected codon: 634 (Cys). Mostly missense mutations. Strong geno-phenotype correlations.

7 Cys634Tyr mutation in a Hungarian MEN2A family Pheo 40 y + MTC 42 y MTC 25 y Sick Healthy Igaz et al., Orvosi Hetilap, 1999

8 Hungarian MEN2A family with a Cys609Ser mutation of Exon10 operation for pheo at 50 y few months later thyreodectomy because of MTC Death: metastatic pheo Index: 48 y operation for pheo calcitonin>780 pg/ml (norm. <11.5), MTC, total thyreoidectomy 14 y, codon 609 mutation prophylactic thyreodectomy pheo neg. Igaz et al., JCEM, 2002, 87, 2994.

9 Genotype-phenotype correlations in MEN2 Medullary thyroid carcinoma (MTC) Agressivity of MTC correlates with mutation type. Class 3 most aggressive mutations: MEN2B (codons 918, 922 and 883), MTC even in a 6-month-old child. Class 2 codons 611, 618, 620 and 634 (MEN2A), less aggressive. Class 1 codons 609, 768, 790, 791, 804 and 891 (MEN2A és FMTC), least aggressive.

10 Proposed age for the prophylactic thyroidectomy Class 3 6 months, perhaps 1 month Classe 2 5 years Class 1 -? Between the ages of 5 and 10 years To perform pentagastrine tests regularly and operate following the first abnormal results.

11 Von Hippel-Lindau disease Autosomal dominant: hereditary (80%) or sporadic (de novo) forms (20%). Tumour-supressor VHL gene - inactivating mutations. 3 big exons Numerous known mutations (>300) all over in the gene Limited genotype-phenotype correlations. In a subset of sporadic forms, mutation analysis from peripheral blood is negative due to mosaicism.

12 Clinical forms of VHL VHL1: renal cysts and carcinoma, retinal and CNS haemangioblastoma, pancreas tumours és cysts, epidydimis cystadenomes. VHL2A: CNS haemangioblastomas, pheo, epidydimis cystadenomas. VHL2B: renal cysts and carcinoma, retinal and CNS haemangioblastomas, pancreas tumours and cysts, pheo, epidydimis cystadenomas. VHL2C: pheo alone.

13 When to perform genetic screening in pheo patients? 1. possibility: in any case Arguments: a.) possibility of tumour syndrome may predispose to other tumours b.) recurrence is more probable in mutation positive cases, possibility of follow-up 2. (more rational approach): patient younger than 50 years, children, bilateral tumours, multifocal, extraadrenal disease, association of other tumours.

14 Mutations of 21-hydroxylase (CYP21) Most frequent cause of congenital adrenal hyperplasia (CAH). Autosomal recessive inheritance. 10 exons. Inactivating mutations. Gene location: MHCIII - CYP21 (CYP21B) and a homologous pseudogene (CYP21P v. CYP21A) The majority of mutations are gene conversions, deletions, partly point mutations.

15 GENETICS ANALYSIS OF ONE OR SOME GENES GENOMICS ANALYSIS OF THE GENOME AS A WHOLE EXPRESSIION PROFILING: FUNCTIONAL GENOMICS STRUCTURAL GENOMICS PROTEOMICS METABOLOMICS