A novel pathogenic mutation of the CYP27B1 gene in a patient with vitamin D-dependent rickets type 1: a case report

Abstract

BackgroundRickets can occur due to Vitamin D deficiency or defects in its metabolism. Three rare genetic types of rickets with different alterations of genes have been reported, including: Vitamin D dependent rickets type 1, Vitamin D dependent rickets type 2 or also known as Vitamin D resistant rickets and 25 hydroxylase deficiency rickets. Vitamin D dependent rickets type 1 is inherited in an autosomal recessive pattern, and is caused by mutations in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. We report here a new mutation in CYP27B1, which lead to Vitamin D dependent rickets type 1.Case presentationWe report on a 13-month-old Arabic Saudi girl with Vitamin D dependent rickets type 1 presented with multiple fractures and classic features of rickets. A whole exome sequencing identified a novel pathogenic missense mutation (CYP27B1:Homozygous c.1510C > T(p.Q504X)) which results in a protein truncating alteration. Both parents are heterozygous carriers of the mutation. Based on data search in Human Gene Mutation Database, 63 CYP27B1 alterations were reported: only 28.6% are protein truncating (5 nonsense, 13 frameshift insertions/deletions, 0 gross deletions), while 61.9% are non-truncating (38 missense, 1 small in-frame insertions/deletion), and 9.5% are possible protein-truncating (5 splice, 1 regulatory).ConclusionThe deleterious effect of this alteration, which was the only mutation detected in the CYP27B1 common gene of Vitamin D dependent rickets type 1 in the proband, and its autosomal recessive inheritance fashion, both support a pathogenic nature of this mutation as the cause of Vitamin D dependent rickets type 1.

A Case of Vitamin D-Dependent Rickets Type 1A with a Novel Mutation in the Uzbek Population

“…VDDR-1A is an autosomal recessive disorder due to an inactivating mutation in the CYP27B1 gene on chromosome 12q14 (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21). The CYP27B1 gene encodes 25(OH) D-1-α-hydroxylase which catalyzes the hormonally regulated, rate limiting step in the bioactivation of vitamin D (1,2,3,4).…”

“…The CYP27B1 gene encodes 25(OH) D-1-α-hydroxylase which catalyzes the hormonally regulated, rate limiting step in the bioactivation of vitamin D (1,2,3,4). Due to blockage of this enzyme activity, normal or elevated 25(OH)D3 level, despite low or low-normal serum 1,25(OH) 2 D 3 , is prominent in VDDR-1A which mimics clinically and radiologically vitamin D deficiency (1,2,3,5). There are no studies on the incidence of vitamin D deficiency in Turkmenistan where our patient lives, but there are reports from countries such as Turkey where nutritional rickets is still encountered (23).…”

“…The CYP27B1 gene is mapped on chromosome 12q14 (4). In different ethnic groups, several mutations (homozygous or compound heterozygous) have been identified in patients with VDDR-1A (3,5,7,8,9,10,11,g,13,14,15,16,17,18,19,20,21). In some ethnic groups, certain mutations are more frequent (2,8,14,20).…”

Genetic and clinical characteristics of the patients with Vitamin D Dependent Rickets Type 1A

“…The second type involves a defective vitamin D receptor (VDR), resulting in vitamin D resistant rickets (VDDR), also known as vitamin D dependent rickets type 2A (VDDR2A). VDBR2B is an unusual form of rickets due to abnormal expression of a hormone response element-binding protein that interferes with normal function of vitamin D receptor (5)(6)(7)(8).…”

Case report: vitamin D‐dependent rickets type 1 caused by a novel CYP27B1 mutation

“…CYP27B1 (MIM #609506), the only gene in which mutations cause VDDR-1, is located on chromosome 12q13.3 [10]. To date, more than 50 different mutations have been reported including missense or nonsense mutations, deletions, splicing mutations, and duplications [11][12][13][14]. The clinical symptoms regress and biochemical findings normalize within months of sufficient treatment with calcitriol, but the necessary dose varies between individuals, which can only in part be explained by molecular studies of the specific mutations [12,15].…”