Background: Acromesomelic dysplasia Maroteaux type (AMDM) (OMIM 602875) is a rare autosomal recessive skeletal disorder with an approximate prevalence of 1/1,000,000) and characterized by severe dwarfism accompanied by shortness of distal and middle segments of extremities. Mutations in the NPR2 gene which encodes for the natriuretic peptide receptor B (NPR-B) is the underlying genetic cause of this disorder.
Objective and hypotheses: Genetic confirmation of AMDM and the identification of the causal mutations in NPR2 gene.
Method: A total of 8 Individuals, belonging to 7 families, diagnosed of AMDM plus relatives were referred from UK, France, India and Spain for genetic analysis. The patients fulfilled clinical and radiological criteria of AMDM and the informed consent was obtained. Molecular genetic study: DNA was extracted from peripheral blood leukocytes by standard techniques. All the coding exons as well as intro-exon boundaries of NPR2 gene were amplified and directly sequenced by Sanger method.
Results: The clinical diagnosis was genetically confirmed in all the patients. Ten novel mutations were identified and each mutation was unique for each patient (P) or family (F) Table 1.
|P||F||Mutation at cDNA level (RefSec NM_003995.3)||Mutation at protein level|
|5||4||c.[2548_2551del]; [.2548_2551del]||p.[Glu850Leufs*32]; [Glu850Leufs*32]|
|7||6||c.[1084_1089del]; [2137A>T]||p.[Leu362_Arg363del]; [Ile713Phe]|
|8||7||c.[1351+7G>A]; [2107C>T]||p.[?]; [Gln703*]|
Conclusion: 1) We have identified ten novel mutations in NPR2 as the cause of AMDM, which broadens the spectrum of inactivating mutations in this gene. 2) These NPR2 mutations are private: unique to individuals and/or families. 3) The identification of the causal mutation in AMDM is important not only to confirm the clinical and radiological diagnosis but to enable a proper genetic counseling and an eventual prenatal diagnosis.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology