A novel variant of IHH in a Chinese family with brachydactyly type 1

Yang, Qi; Wang, Jin; Tian, Xiaoxian; Shen, Fei; Lan, Jing; Zhang, Qiang; Fan, Xin; Shang, Yue; Li, Mengting; Shen, Yiping

doi:10.1186/s12881-020-01000-6

Cited by 7 publications

(7 citation statements)

References 21 publications

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“…BDA1 is inherited in an autosomal dominant manner and is characterized by hypoplasia or aplasia of the middle phalanges of digits 2–5. Approximately half of the analysed BDA1 cases are due to mutations in IHH [ 1 ]. The Hedgehog (Hh) family of secreted proteins regulates various developmental processes, maintains adult tissue homeostasis, and functions as a morphogen gradient [ 15 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

“…A short stature of variable severity was observed among the Japanese family. Yang et al [ 1 ] summarized several case reports of BDA1 and concluded that short stature was present only with IHH variants at Asp100. Affected siblings (V-4, 6) fell under the category of normal stature, although they were relatively short in height.…”

Section: Discussionmentioning

confidence: 99%

“…The middle phalanges are either rudimentary or fused with the terminal phalanges. Approximately half of BDA1 cases are due to variants in the Indian Hedgehog ( IHH ) gene [ 1 ]. As a central signalling molecule mediating skeletal development, IHH plays an important role in modulating skeletal condensation, the growth and differentiation of chondrocytes, joint development and bone formation [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…This is interpreted as a common mechanism of the BDA1-causing variants [4]. Most IHH variants have been characterized as missense [1,3,[5][6][7][8][9][10][11][12], except for one insertion [13] and one deletion [14].…”

Section: Introductionmentioning

confidence: 99%

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Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1

Ozaki¹,

Okuda

Kobayashi

et al. 2021

BMC Med Genomics

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Background Brachydactyly type A1 (BDA1) is an autosomal dominant disorder characterized by uniform shortening of the middle phalanges in all digits. It is associated with variants in the Indian Hedgehog (IHH) gene, which plays a key role in endochondral ossification. To date, heterozygous pathogenic IHH variants involving several codons, which are restricted to a specific region of the N-terminal active fragment of IHH, have been reported. The purpose of this study was to identify the pathogenic variant in a Japanese family with BDA1 and to evaluate its pathogenesis with regard to previous reports. Methods The proband, a 9-year-old boy, his siblings, and his father had shortened digits and a short stature of variable severity. Based on physical examinations, radiographic findings and family history, they were diagnosed with BDA1. This family is the first case of an isolated malformation in Japan. Sanger sequencing of IHH was performed on these individuals and on the proband’s unaffected mother. The significance of the variants was assessed using three-dimensional analysis methods. Results Sanger sequencing showed a novel IHH heterozygous variant, NM_002181.4:c.544_549delTCAAAG(p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del].. These two residues are located outside the cluster region considered a hotspot of pathogenic variants. Three-dimensional modelling showed that S182 and K183 are located on the same surface as other residues associated with BDA1. Analysis of residue interactions across the interface between IHH and its interacting receptor protein revealed the presence of hydrogen bonds between them. Conclusions We report a novel variant, NM_002181.4:c.544_549delTCAAAG (p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del] in a Japanese family with BDA1. Indeed, neither variations in codons 182 or 183 nor with such two-amino-acid deletions in IHH have been reported previously. Although these two residues are located outside the cluster region considered a hotspot of pathogenic variants, we speculate that this variant causes BDA1 through impaired interactions between IHH and target receptor proteins in the same manner as other pathogenic variants located in the cluster region. This report expands the genetic spectrum of BDA1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1

Ozaki¹,

Okuda

Kobayashi

et al. 2021

BMC Med Genomics

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“…Genetic attribution of BDA1 to IHH mutations was first revealed in 2001 ( Gao et al, 2001 ). Since then, increasing genetic evidence has shown that several mutations have been identified in IHH , whose protein product plays a critical role in growth, patterns, and morphogenesis ( Gao et al, 2001 ; Giordano et al, 2003 ; Byrnes et al, 2009 ; Jang et al, 2015 ; Ho et al, 2018 ; Shen et al, 2019 ; Yang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: Brachydactyly Type A1 Induced by a Novel Variant of in-Frame Insertion in the IHH Gene

et al. 2022

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Brachydactyly type A1 (BDA1) is an autosomal dominant inherited disease characterized by the shortness/absence of the middle phalanges, which can be induced by mutations in the Indian hedgehog gene (IHH). Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by joint destruction, synovitis, and the presence of autoantibodies. In this study, the proband was diagnosed with both BDA1 and RA. We performed whole-exome sequencing in a four-generation Chinese family to investigate their inherited causal mutation to BDA1. A novel in-frame insertion variant in IHH: NM_002,181.4: c.383_415dup/p.(R128_H138dup) was identified in the BDA1 pedigree. This insertion of 11 amino acids was located in the highly conserved amino-terminal signaling domain of IHH and co-segregated with the disease status. This adds one to the total number of different IHH mutations found to cause BDA1. Moreover, we found a potential causal germline variant in CRY1 for a molecular biomarker of RA (i.e., a high level of anti-cyclic citrullinated peptide). Collectively, we identified novel variants in IHH for inherited BDA1, which highlights the important role of this gene in phalange development.

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A Novel Heterozygous IHH c.331_333del Mutation Identified in a Fetus with Brachydactyly Type A1 Causes IHH Protein Maturation Failure in HEK293T Cells

Zhu,

Guan,

Chen

et al. 2024

Phenomics

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Brachydactyly A1 (BDA1) is a rare disorder characterized by the disproportionate shortening of fingers and/or toes with or without symphalangism. Mutations in Indian hedgehog signaling molecule (IHH), which impair the effect of functional IHH protein derived from its precursor IHH, are commonly identified in patients with BDA1 or acrocapitofemoral dysplasia (ACFD). The ultrasound phenotype of fetuses with IHH mutations has rarely been described. To better understand the consequences of IHH mutation, we analyzed the characteristics of a Chinese fetus with BDA1 caused by a novel heterozygous IHH mutation. Clinical data and genomic DNA were collected from the proband and family members. Whole-exome sequencing (WES) was performed to identify potential causative mutations. Sequence analysis was performed to investigate the conservation of the affected leucine residue in IHH. Protein 3D modeling was performed to predict the effects of the mutation on protein structure. In vitro overexpression transfection experiments in human embryonic kidney 293T (HEK293T) cell lines were performed to evaluate the pathogenicity of the identified mutation. The fetal proband carried a novel heterozygous mutation in IHH (NM_002181.4: c.331_333delCTG, NP_002172.2: p.Leu111del) inherited from the father; this mutation manifested as shortening of the limbs, with more severe shortening observed in the proximal extremities than in the distal extremities, as evidenced by ultrasound. The Leu111 residue is highly conserved among vertebrates, and deletion of this residue destabilizes the protein structure. Western blotting analysis of HEK293T cells in overexpression transfection experiments revealed that the Leu111del mutation led to an increase in the level of the IHH precursor and a reduction in the level of functional IHH protein compared with those in HEK293T cells expressing wild-type IHH, indicating that this mutation might cause IHH protein dysmaturity. The novel heterozygous mutation c.331_333delCTG (p.Leu111del) in the IHH gene is the likely cause of BDA1 in this Chinese fetus. This mutation causes IHH protein maturation failure. These findings contribute to our understanding of the molecular pathogenesis of BDA1 and the clinical identification of fetal BDA1.

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A novel variant of IHH in a Chinese family with brachydactyly type 1

Cited by 7 publications

References 21 publications

Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1

Deletion of 2 amino acids in IHH in a Japanese family with brachydactyly type A1

Case Report: Brachydactyly Type A1 Induced by a Novel Variant of in-Frame Insertion in the IHH Gene

A Novel Heterozygous IHH c.331_333del Mutation Identified in a Fetus with Brachydactyly Type A1 Causes IHH Protein Maturation Failure in HEK293T Cells

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