Levy-Khademi Floris, Zeligson Sharon, Lavi Eran, Klopstock Tehila, Chertin Boris, Avnon-Ziv Carmit, Abulibdeh Abdulsalam, Renbaum Paul, Rosen Tzvia, Perlberg-Bengio Shira, Zahdeh Fouad, Behar Doron M, Levy-Lahad Ephrat, Zangen David, Segel Reeval
Division of Pediatric Endocrinology, Department of Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel.
The Hebrew University School of Medicine, Jerusalem, Israel.
Endocrine. 2020 Sep;69(3):650-654. doi: 10.1007/s12020-020-02327-z. Epub 2020 May 5.
Mutations in the gene HSD17B3 encoding the 17-beta hydroxysteroid dehydrogenase 3 enzyme cause testosterone insufficiency leading to XY disorders of sex development. In this study the clinical and molecular characteristics of three patients from consanguineous families are elucidated.
We identified three patients from two unrelated families with XY DSD and a novel homozygous HSD17B3:c. 673G>A mutation. The effect of the mutation on splicing was determined in RNA extracted from the testis of one patient.
Three patients presented at ages 0.1, 8 and 0.7 years with ambiguous genitalia and an XY Karyotype. Endocrine workup showed normal cortisol and mineralocorticoid levels with a low testosterone/androstenedione ratio. Whole-exome sequencing, carried out in the first family, revealed a homozygous novel mutation in the HSD17B3 gene: c. 673G>A, p. V225M. The same mutation was found by Sanger sequencing in the third unrelated patient. Haplotype analysis of a 4 Mb region surrounding the HSD17B3 gene on chromosome 9 revealed that the mutation resides on the same allele in all three patients. The mutation, being the first nucleic acid on exon 10, affects splicing and causes exon 10 skipping in one of our patients' testes.
The novel homozygous c. 673G>A, p. V225M mutation in the 17HSDB3 gene is likely a founder mutation and causes severe XY-DSD. It changes a conserved amino acid residue, and also alters 17HSDB3 gene transcription by causing skipping of exon 10, thereby contributing to an imbalance in the relevant protein isoforms and consequently, significant decreased 17HDSB3 enzymatic activity.
编码17-β羟类固醇脱氢酶3的HSD17B3基因突变会导致睾酮分泌不足，从而引发XY性发育障碍。在本研究中，对来自近亲家庭的三名患者的临床和分子特征进行了阐述。
我们从两个无关家庭中鉴定出三名患有XY性发育障碍（XY DSD）且携带新型纯合HSD17B3:c. 673G>A突变的患者。从一名患者的睾丸中提取RNA，确定该突变对剪接的影响。
三名患者分别在0.1岁、8岁和0.7岁时出现生殖器模糊和XY核型。内分泌检查显示皮质醇和盐皮质激素水平正常，但睾酮/雄烯二酮比值较低。对第一个家庭进行的全外显子组测序揭示了HSD17B3基因中的一个纯合新突变：c. 673G>A，p. V225M。在第三名无关患者中通过桑格测序发现了相同的突变。对9号染色体上HSD17B3基因周围4 Mb区域的单倍型分析表明，该突变存在于所有三名患者的同一个等位基因上。该突变是外显子10上的第一个核酸，影响剪接并导致我们其中一名患者的睾丸中出现外显子10跳跃。
17HSDB3基因中的新型纯合c. 673G>A，p. V225M突变可能是一个奠基者突变，并导致严重的XY-DSD。它改变了一个保守的氨基酸残基，还通过导致外显子10跳跃改变了17HSDB3基因转录，从而导致相关蛋白质异构体失衡，进而显著降低17HDSB3酶活性。
