Molecular study of NPC-1 and NPC-2 genes, associated with Niemann-Pick type C disease, in selected subgroups of the Greek population

Doctoral Dissertation uoadl:2801832 184 Read counter

Τομέας Υγείας - Μητέρας - Παιδιού
Library of the School of Health Sciences
Deposit date:
Bountouvi Evangelia
Dissertation committee:
Βασιλική Παπαευαγγέλου, Καθηγήτρια, Ιατρική, ΕΚΠΑ
Αναστάσιος Παπαδημητρίου, Καθηγητής, Ιατρική, ΕΚΠΑ
Γεώργιος Τσιβγούλης, Καθηγητής, Ιατρική, ΕΚΠΑ
Αργύριος Ντινόπουλος, Αναπληρωτής Καθηγητής, Ιατρική, ΕΚΠΑ
Αχιλλέας Αττιλάκος, Επίκουρος Καθηγητής, Ιατρική, ΕΚΠΑ
Γεώργιος Βάρτζελης, Επίκουρος Καθηγητής, Ιατρική, ΕΚΠΑ
Μαρία-Ροζέ Πονς-Ροντρίγκεθ, Επίκουρη Καθηγήτρια, Ιατρική, ΕΚΠΑ
Original Title:
Μελέτη των γονιδίων NPC-1 και NPC-2, τα οποία σχετίζονται με τη νόσο Niemann-Pick τύπου C, σε επιλεγμένες υποομάδες του ελληνικού πληθυσμού
Translated title:
Molecular study of NPC-1 and NPC-2 genes, associated with Niemann-Pick type C disease, in selected subgroups of the Greek population
Background: Niemann-Pick type C disease (NPC) is an autosomal recessive, neurovisceral, lysosomal storage disorder with protean and progressive clinical manifestations, resulting from mutations in either of the two genes, NPC1 (~95% of families) and NPC2. Contrary to other populations, published evidence regarding NPC disease in Greece is sparse.
Methods: The study population consisted of three groups: a) 37 Greek individuals with high clinical suspicion for the disease recruited in a 4-year period, via questionnaires completed by attendant physicians from 10 hospitals over Greece (SGs); b) two Greek biochemically diagnosed NPC patients –identified during recruitment- and their extended pedigrees (NPC/RG1-2); c) 90 healthy Greek individuals (CG). Genotyping was performed in the SGs and NPC patients by direct sequencing of the NPC1 and –in selected cases- the NPC2. Targeted gene variations were studied in the NPC patients’ relatives and the control group. The origin of two novel mutations was investigated through selected exonic NPC1 polymorphisms, encountered more frequently in the SGs and in the CG, by the use of Haplore software.
Results: Overall, 26 genetic variations were identified, 24 in NPC1 and 2 in NPC2. Among them, three NPC1 pathogenic mutations [IVS23+3insT (c.3591+3insT), p.K1057R (c.3170A>G) and p.Α1132Ρ (c.3394G>C)], two novel NPC1 intronic non-pathogenic alterations (IVS7-16C>T and IVS20+22G>C) and two rare genetic alterations of equivocal clinical significance (c.709C>T; rs80358251 in NPC1 and c.441+1G>A; rs140130028 in NPC2) were detected. The two novel mutations [IVS23 + 3insT (c.3591 + 3insT), p.K1057R (c.3170A > G)] were each associated with a specific haplotype. The distribution of p.M642I (rs1788799) in the Suspicion Group varied significantly compared to the control group. NPC patients’ clinical, biochemical, molecular profiles and the possible correlations are presented. One NPC patient was entered to early treatment with miglustat and has presented no overt neurological impairment after 11.5 years.
Conclusions: Sequence variations of NPC genes were genotyped for first time in Greek individuals. The frequency and the type of the exonic polymorphisms observed in this subgroup of Greek population are mainly in accordance with other European populations.NPC patient 1 was compound heterozygous for two novel mutations [IVS23 + 3insT (c.359 +3insT), p.K1057R (c.3170A>G)]. The splicing mutation IVS23+3insT was associated in homozygocity with a severe biochemical and clinical phenotype and the missense mutation p.K1057R (c.3170A>G) with the severe biochemical pattern. A possible founder effect for IVS23+3insT mutation was demonstrated in the Greek Island, as well as a different origin for each novel mutation. Longitudinal follow-up may contribute to clarify the possible effect of early miglustat therapy on the patient compound heterozygous for the two novel mutations. Furthermore, the mutant allele p.A1132P was associated in homozygocity with a severe biochemical phenotype and the infantile form of the disease. The patient, homozygous for this mutation, has been under miglustat therapy and exhibited progressive neurological deterioration. In this context, and as an extension of the present study, she also receives 2-hydroxy-propyl-cyclodextrin as well as another NPC patient with positive results.
Main subject category:
Health Sciences
Niemann-Pick type C disease, Novel mutations, Polymorphisms, Therapy, Miglustat, Greek population
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