A novel mutation of HOXA11 in a patient with septate uterus

Zhu, Ying; Cheng, Zhi; Wang, Jing; Liu, Beihong; Cheng, Longfei; Chen, Beili; Cao, Yunxia; Wang, Binbin

doi:10.1186/s13023-017-0727-9

Cited by 12 publications

(7 citation statements)

References 40 publications

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“…Our patient had normal blood counts and elbow joint movements. Moreover, a heterozygous variant in HOXA11 , c.763G>A (p.Glu255Lys) has been reported as potentially cause of isolated septate uterus and spontaneous abortions but not additional anomalies in the limbs or urogenital system (Zhu et al, 2017). Another homozygous HOXA11 variant, c.775G>A (p.Glu259Lys), was recently reported as a new cause of autosomal recessive congenital anomalies of the kidney and urinary tract.…”

Section: Discussionmentioning

confidence: 99%

“…All of the reported variants in HOXA11 are located in the homeobox domain (Figure 2e). Some reports underlined that two variants, p.Asn291ThrfsTer4, and p.Glu255Lys affected the DNA‐binding ability of HOXA11 (Horvat‐Switzer & Thompson, 2006; Zhu et al, 2017). For the variant p.Asn291ThrfsTer4 related to RUSAT, the mechanism was suggested as either haploinsufficiency or a combination of haploinsufficiency and dominant‐negative effect (Horvat‐Switzer & Thompson, 2006).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A de novo heterozygous HOXA11 variant in a patient with mesomelic dysplasia with urogenital abnormalities

Sezer

Perçin

Kazan

et al. 2022

American J of Med Genetics Pt A

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Mesomelic dysplasias are a genetically and clinically heterogeneous group of diseases with more than 10 types defined. This article presents an 18-year-old female patient with normal intelligence and a multisystem phenotype including disproportionate short stature, scoliosis, mesomelic limb shortening, radial bowing, short fourth to fifth metacarpals and metatarsals, fusions in the carpal/tarsal bones, operated pes equinovarus, primary amenorrhea, uterine hypoplasia, vesicoureteral reflux, and chronic kidney disease. Whole-exome sequencing revealed a de novo heterozygous c.881T>G (p.Met294Arg) variant in HOXA11 (NM_005523.6) gene. The variant was located in the homeodomain of HOXA11 and predicted to alter DNA-binding ability of the protein. In silico analyses indicated that the variant could promote the alterations in the protein-protein interaction. The possible functional effect of the variant was supposed as dominant-negative. Hoxa11-mutant mice have been reported to exhibit homeotic transformations in the thoracic and sacral vertebrae, zeugopodal phenotype in forelimb and hindlimb, and urogenital abnormalities. Although mice models were reported as mesomelic dysplasia and urogenital abnormalities (MDUGA), this phenotype has not yet been reported in humans. This was the first case with MDUGA putatively related to a de novo variant in HOXA11.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A de novo heterozygous HOXA11 variant in a patient with mesomelic dysplasia with urogenital abnormalities

Sezer

Perçin

Kazan

et al. 2022

American J of Med Genetics Pt A

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“…The expression of HOXA10 was downregulated in the endometrium of MDA patients ( Zhu et al, 2016 ), and pathogenic mutations in HOXA10 have been linked to women with MDAs ( Ekici et al, 2013 ). Also, a causative mutation in HOXA11 was found in a patient with septate uterus ( Zhu et al, 2017 ). The functions of Hox genes have also been extensively investigated using mouse models.…”

Section: Technologies and Strategies To Investigate Mda Genetics And Genomicsmentioning

confidence: 99%

Studying Müllerian duct anomalies – from cataloguing phenotypes to discovering causation

González

Artibani

Ahmed

2021

Disease Models &Amp; Mechanisms

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Müllerian duct anomalies (MDAs) are developmental disorders of the Müllerian duct, the embryonic anlage of most of the female reproductive tract. The prevalence of MDAs is 6.7% in the general female population and 16.7% in women who exhibit recurrent miscarriages. Individuals affected by these anomalies suffer from high rates of infertility, first-trimester pregnancy losses, premature labour, placental retention, foetal growth retardation and foetal malpresentations. The aetiology of MDAs is complex and heterogeneous, displaying a range of clinical pictures that generally lack a direct genotype-phenotype correlation. De novo and familial cases sharing the same genomic lesions have been reported. The familial cases follow an autosomal-dominant inheritance, with reduced penetrance and variable expressivity. Furthermore, few genetic factors and molecular pathways underpinning Müllerian development and dysregulations causing MDAs have been identified. The current knowledge in this field predominantly derives from loss-of-function experiments in mouse and chicken models, as well as from human genetic association studies using traditional approaches, such as microarrays and Sanger sequencing, limiting the discovery of causal factors to few genetic entities from the coding genome. In this Review, we summarise the current state of the field, discuss limitations in the number of studies and patient samples that have stalled progress, and review how the development of new technologies provides a unique opportunity to overcome these limitations. Furthermore, we discuss how these new technologies can improve functional validation of potential causative alterations in MDAs.

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“…Familial septate uterus or septate uterus with other malformations have also been reported, but very rare. Previous studies have found that the mutations of HOXA10 , and HOXA11 genes are associated with the occurrence of septate uterus, but all of them are sporadic cases, lacking familial studies on the genetics of septate uterus.…”

Section: Introductionmentioning

confidence: 99%

Sequence variant in the CDC42BPB gene is potentially associated with Mullerian duct anomalies

Luo

Feng

et al. 2020

J of Obstet and Gynaecol

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Aim: Mullerian duct anomalies (MDA) are common female genital tract malformations. Genetic and environmental factors are important causes of MDA in women. Although many genes and mutations have been found to be associated with the pathogenesis of MDA, in most cases, the genetic pathogenic factors of MDA are still unknown. Methods: We first analyzed the three sisters using low coverage whole-genome sequencing. Then wholeexome sequencing was carried out in each patient. The identified sequence variant was confirmed by Sanger sequencing. In silico pathogenicity analysis and conservative analysis of the mutation site were also performed. Protein structural modeling was used to analyze the effect of the mutated amino acid. Results: We first analyzed the three sisters with septate uterus using low coverage whole-genome sequencing, but no possible pathogenic copy number variation was found. Then whole-exome sequencing was performed on the three sisters, and a rare homozygous variant, CDC42BPB:c.2012G>A:p.R671Q, was identified. All three patients were found with this variant. Sanger sequencing validated that this variant was segregated within the family. In silico pathogenicity analysis and conservative analysis of the mutation site suggested that the variant might be damaging. Protein structural analysis suggested that R671Q might weaken the electrostatic potential of this region, which may be a significant regulation target or protein interaction surface of CDC42BPB. Conclusion: We demonstrated that CDC42BPB genetic variant might be potentially associated with the pathogenesis of MDA.

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A novel mutation of HOXA11 in a patient with septate uterus

Cited by 12 publications

References 40 publications

A de novo heterozygous HOXA11 variant in a patient with mesomelic dysplasia with urogenital abnormalities

A de novo heterozygous HOXA11 variant in a patient with mesomelic dysplasia with urogenital abnormalities

Studying Müllerian duct anomalies – from cataloguing phenotypes to discovering causation

Sequence variant in the CDC42BPB gene is potentially associated with Mullerian duct anomalies

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