Mystery(n) Phenotypic Presentation in Europeans: Report of Three Further Novel Missense RNF213 Variants Leading to Severe Syndromic Forms of Moyamoya Angiopathy and Literature Review

被引：3

作者：

Santoro, Claudia ^{[1
,2
]}

Mirone, Giuseppe ^{[3
]}

Zanobio, Mariateresa ^{[4
]}

Ranucci, Giusy ^{[5
]}

D'Amico, Alessandra ^{[6
]}

Cicala, Domenico ^{[3
]}

Iascone, Maria ^{[7
]}

Bernardo, Pia ^{[8
]}

Piccolo, Vincenzo ^{[9
]}

Ronchi, Andrea ^{[10
]}

Limongelli, Giuseppe ^{[11
]}

Carotenuto, Marco ^{[1
]}

Nigro, Vincenzo ^{[4
,12
]}

Cinalli, Giuseppe ^{[3
]}

Piluso, Giulio ^{[4
]}

机构：

[1] Univ Campania Luigi Vanvitelli, Dept Mental & Phys Hlth & Prevent Med, Child & Adolescent Neuropsychiat Clin, Via Pansini 5, I-80131 Naples, Italy

[2] Univ Campania Luigi Vanvitelli, Dept Womens & Childrens Hlth & Gen & Specialized, Via Crecchio 4, I-80138 Naples, Italy

[3] Santobono Pausilipon Childrens Hosp, AORN, Dept Neurosci, Via Ravaschieri 8, I-80122 Naples, Italy

[4] Univ Campania Luigi Vanvitelli, Dept Precis Med, Via Luigi Crecchio 7, I-80138 Naples, Italy

[5] Santobono Pausilipon Childrens Hosp, Dept Pediat, AORN, Via Ravaschieri 8, I-80122 Naples, Italy

[6] Tortorella Private Hosp, Dept Radiol, Via Aversano 1, I-84214 Salerno, Italy

[7] ASST Papa Giovanni XXIII, Med Genet Lab, Piazza OMS 1, I-24127 Bergamo, Italy

[8] Santobono Pausilipon Childrens Hosp, AORN, Dept Neurosci Pediat Psychiat & Neurol, Via Ravaschieri 8, I-80122 Naples, Italy

[9] Univ Campania Luigi Vanvitelli, Dermatol Unit, Via Pansini 5, I-80131 Naples, Italy

[10] Univ Campania Luigi Vanvitelli, Anat Pathol Unit, Piazza Miraglia 2, I-80138 Naples, Italy

[11] Univ Campania Luigi Vanvitelli, Monaldi Hosp, Div Cardiol, Via Bianchi, I-80131 Naples, Italy

[12] Telethon Inst Genet & Med, Via Campi Flegrei 34, I-80078 Pozzuoli, Italy

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2022年 / 23卷 / 16期

基金：

欧盟地平线“2020”;

关键词：

RNF213; moyamoya; whole exome sequencing; hypertransaminasemia; livedo reticularis; annular figurate erythema; skin; hypertension; DISEASE; ASSOCIATION;

D O I：

10.3390/ijms23168952

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred de novo (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband's carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in RNF213 cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118-4122 and 4867 of RNF213 could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations.

引用

页数：17