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A homozygous G insertion in MPLKIP leads to TTDN1 with the hypergonadotropic hypogonadism symptom.

ABSTRACT: BACKGROUND:Trichothiodystrophy nonphotosensitive 1 (TTDN1) is a disease with mental retardation, brittle hair. Some cases of the diseases are caused by mutations of the MPLKIP gene. METHODS:We carefully identified the clinic characteristics, the sulfur level and pattern of the hair shafts of a female patient of with the symptom of hypergonadotropic hypogonadism, and of her parents and brother whose are healthy. We also collected the blood sample of the patient and performed the exon sequencing. One G insertion in MPLKIP was identified after analyzing the obtained exon sequencing profile. The G insertion sites in the patient, her parents and brother, were verified using Sanger sequencing. The G insertion in MPLKIP were compared to the dbSNP. RESULTS:The female patient of TTDN1 carries a homozygous G insertion (rs747470385) in the MPLKIP gene. The parents and brother of the patient are heterozygous carriers of the same mutation, but are healthy. The hair shafts of the patient had a tiger-tail pattern with relatively low sulfur levels. To the best of our knowledge, this is the first report that autosomal recessive inheritance of the G insertion in the MPLKIP gene results in TTDN1. CONCLUSION:Our results indicate that the homozygotic G insertion in MPLKIP results in the TTDN1 with hypergonadotropic hypogonadism, while heterozygous carriers of the same mutation have no symptoms and healthy. These results provide novel insights into the association of mutations in MPLKIP and TTDN1 with hypergonadotropic hypogonadism.

SUBMITTER: Zhou YK

PROVIDER: S-EPMC6311919 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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A homozygous G insertion in MPLKIP leads to TTDN1 with the hypergonadotropic hypogonadism symptom.

Zhou Yi-Kun YK Yang Xiao-Chun XC Cao Yang Y Su Heng H Liu Li L Liang Zhi Z Zheng Yun Y

BMC medical genetics 20181231 Suppl 1

<h4>Background</h4>Trichothiodystrophy nonphotosensitive 1 (TTDN1) is a disease with mental retardation, brittle hair. Some cases of the diseases are caused by mutations of the MPLKIP gene.<h4>Methods</h4>We carefully identified the clinic characteristics, the sulfur level and pattern of the hair shafts of a female patient of with the symptom of hypergonadotropic hypogonadism, and of her parents and brother whose are healthy. We also collected the blood sample of the patient and performed the ex ...[more]

PMID: 30598092

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Project description:Abstract Background Hypergonadotropic hypogonadism can be caused by congenital or acquired causes. These can range from chromosomal abnormalities, enzymatic defects or mutations that cause gonadotropin resistance, trauma, chemotherapy, infections etc. It is uncommon in females other than in Turner syndrome and not all the genetic etiologies are known. Clinical Case A 15 10/12 year old female with primary amenorrhea and absent pubertal development presented with FSH and LH levels of 35.24 mIU/mL and 14.38 mIU/mL, respectively and non-pubertal estradiol levels of 4 pg/mL consistent with hypergonadotropic hypogonadism. Her evaluation showed a normal 46,XX female karyotype and no evidence of hyperandrogenism or thyroid dysfunction. Ultrasound showed no evidence of ovaries and a rudimentary uterus measuring 0.9 cm×1.4 cm×1.2 cm with a delayed bone age of 12 years. Family history was positive for mother having delayed puberty with menarche at 16.5 years of age. Patient was started on hormone replacement therapy with transdermal estrogen. Four months after treatment she developed breast buds and vaginal discharge. After 1.5 years, the uterus measurements were 5.7 cm x3.7 cm x2.2 cm although no ovarian tissue or follicles were identified on MRI. Her biochemical profile also showed decreases in FSH (3.48 mIU/mL) and LH (0.99 mIU/mL) and an increase in estradiol (38pg/mL). Exome sequencing was performed and revealed biallelic missense variants c.766C>T, p.(Pro256Ser) and c.1036G>C p.(Gly346Arg) in exon 2 of the INHA (NM_002191) gene. Both variants are rare in the human population, seen in a heterozygous state with a global allele frequency (gnomADv2.1) of 0 and 0.00002790 (rs780833794), respectively, and predicted to be damaging by bioinformatic tools. INHA, a member of the transforming growth factor-β (TGF-β) superfamily, encodes the alpha subunit of glycoprotein hormones inhibin A and B. Studies in animal models indicate that inhibin A negatively regulates follicle stimulating hormone (FSH) secretion by suppressing FSHR expression and plays a crucial role in ovarian steroid hormone production, follicular development, proliferation and apoptosis of granulosa cells, and oocyte maturation. Heterozygous pathogenic variants in the INHA gene have been reported in patients with primary ovarian insufficiency (POI) and secondary amenorrhea1, while our patient with biallelic variants in INHA is affected by gonadal dysgenesis, primary amenorrhea, absence of puberty, a more severe POI phenotype. Conclusion To our knowledge, this is the first case of biallelic mutations in INHA gene leading to a severe phenotype (gonadal dysgenesis, primary amenorrhea and absence of puberty) compared to heterozygous mutations that lead to POI with secondary amenorrhea. 1References: Marozzi A, Porta C, et al. 2002. Mutation analysis of the inhibin alpha gene in a cohort of Italian women affected by ovarian failure. Human Reproduction Vol. 17 No.7 1741-1745 Presentation: Monday, June 13, 2022 12:30 p.m. - 12:35 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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A homozygous G insertion in MPLKIP leads to TTDN1 with the hypergonadotropic hypogonadism symptom.

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A homozygous G insertion in MPLKIP leads to TTDN1 with the hypergonadotropic hypogonadism symptom.

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