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Identification of p.Glu131Lys Mutation in the IHH Gene in a Korean Patient With Brachydactyly Type A1.

Jang MA, Kim OH, Kim SW, Ki CS - Ann Lab Med (2015)

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

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Dear Editor Brachydactyly is a heterogeneous group of inherited disorders of the digits, characterized by shortened fingers and/or toes... Among them, brachydactyly type A1 (BDA1; MIM 112500) is characterized by bilaterally symmetrical shortening or absence of the middle phalanges of most digits... A 32-yr-old man with shortening of digits on both hands and feet presented to our hospital for evaluation... He was of normal stature and development compared with general Korean standards... PCR products were sequenced on an ABI 3730×lDNA Analyzer (Applied Biosystems, Foster City, CA, USA) by using a BigDye Terminator v3.1 Cycle sequencing kit (Applied Biosystems)... Sequences were analyzed by using Sequencher software (Gene Codes Corp., Ann Arbor, MI, USA) and compared with the reference sequence for IHH (NM_002181.3)... In the Chinese family with the p.Glu131Lys variant, the involved brachydactyly sites varied among the different family members as did other hand anomalies such as shortened proximal phalanges of the thumbs and clinodactyly, which suggests the phenotypic variability of BDA1... The Ihh gene, which encodes a member of the Hedgehog family of secreted signaling molecules, is known for its role in mediating condensation, growth, and differentiation of long bone cartilage templates... In an experiment involving Ihh -/- mice, loss of Ihh signaling resulted in a limb reduction phenotype, with a complete lack of osteoblast development in all bones that develop by endochondral ossification, highlighting the role played by Ihh in cartilage differentiation and bone formation... To date, 10 different missense mutations and one deletion have been identified in the Human Gene Mutation Database (HGMD, 2014.3)... Almost all BDA1-causing IHH mutations are missense mutations and are restricted to the N-terminal active fragment spanning codons 95-154. p.Glu131Lys mutation located in the N-terminal fragment affects Hedgehog binding to the receptor Patched1, reducing its capacity to induce cellular differentiation... In conclusion, we identified p.Glu131Lys mutation in the IHH gene.

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Sequence analysis of the IHH gene. A heterozygous mutation of c.391G>A (p.Glu131Lys) in exon 2 is noted.
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Figure 2: Sequence analysis of the IHH gene. A heterozygous mutation of c.391G>A (p.Glu131Lys) in exon 2 is noted.

Mentions: A 32-yr-old man with shortening of digits on both hands and feet presented to our hospital for evaluation. He was of normal stature and development compared with general Korean standards. His prenatal history was unremarkable. The range of motion of his hand joints was normal, and he had no other skeletal or non-skeletal dysmorphisms. The proband's father (I-1) and his two sisters (II-2 and II-3) also had brachydactyly (Fig. 1A). The first sister had two affected children (III-1 and III-3) (Fig. 1A). Radiographs of the proband showed the absence of the 2nd-5th middle phalanges and hypoplastic proximal phalanges in both hands and feet (Fig. 1B), characteristic of BDA1. Although genetic heterogeneity of BDA1 has been documented, most of the reported affected families carried a mutation in the IHH gene; thus, we analyzed the IHH gene sequence. Informed consent was obtained, and whole blood was collected from the patient, in EDTA vacutainer. Genomic DNA was extracted from peripheral blood leukocytes, and all three coding exons were amplified by PCR using primers that we designed (available on request). PCR products were sequenced on an ABI 3730√ólDNA Analyzer (Applied Biosystems, Foster City, CA, USA) by using a BigDye Terminator v3.1 Cycle sequencing kit (Applied Biosystems). Sequences were analyzed by using Sequencher software (Gene Codes Corp., Ann Arbor, MI, USA) and compared with the reference sequence for IHH (NM_002181.3). A missense mutation in the IHH gene (c.391G>A; p.Glu131Lys) was identified in the patient (Fig. 2). Other affected individuals (I-1, II-2, II-3, III-1, and III-3) refused the genetic test; thus, a family study could not be conducted in this case.


Identification of p.Glu131Lys Mutation in the IHH Gene in a Korean Patient With Brachydactyly Type A1.

Jang MA, Kim OH, Kim SW, Ki CS - Ann Lab Med (2015)

Sequence analysis of the IHH gene. A heterozygous mutation of c.391G>A (p.Glu131Lys) in exon 2 is noted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390715&req=5

Figure 2: Sequence analysis of the IHH gene. A heterozygous mutation of c.391G>A (p.Glu131Lys) in exon 2 is noted.
Mentions: A 32-yr-old man with shortening of digits on both hands and feet presented to our hospital for evaluation. He was of normal stature and development compared with general Korean standards. His prenatal history was unremarkable. The range of motion of his hand joints was normal, and he had no other skeletal or non-skeletal dysmorphisms. The proband's father (I-1) and his two sisters (II-2 and II-3) also had brachydactyly (Fig. 1A). The first sister had two affected children (III-1 and III-3) (Fig. 1A). Radiographs of the proband showed the absence of the 2nd-5th middle phalanges and hypoplastic proximal phalanges in both hands and feet (Fig. 1B), characteristic of BDA1. Although genetic heterogeneity of BDA1 has been documented, most of the reported affected families carried a mutation in the IHH gene; thus, we analyzed the IHH gene sequence. Informed consent was obtained, and whole blood was collected from the patient, in EDTA vacutainer. Genomic DNA was extracted from peripheral blood leukocytes, and all three coding exons were amplified by PCR using primers that we designed (available on request). PCR products were sequenced on an ABI 3730√ólDNA Analyzer (Applied Biosystems, Foster City, CA, USA) by using a BigDye Terminator v3.1 Cycle sequencing kit (Applied Biosystems). Sequences were analyzed by using Sequencher software (Gene Codes Corp., Ann Arbor, MI, USA) and compared with the reference sequence for IHH (NM_002181.3). A missense mutation in the IHH gene (c.391G>A; p.Glu131Lys) was identified in the patient (Fig. 2). Other affected individuals (I-1, II-2, II-3, III-1, and III-3) refused the genetic test; thus, a family study could not be conducted in this case.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Dear Editor Brachydactyly is a heterogeneous group of inherited disorders of the digits, characterized by shortened fingers and/or toes... Among them, brachydactyly type A1 (BDA1; MIM 112500) is characterized by bilaterally symmetrical shortening or absence of the middle phalanges of most digits... A 32-yr-old man with shortening of digits on both hands and feet presented to our hospital for evaluation... He was of normal stature and development compared with general Korean standards... PCR products were sequenced on an ABI 3730×lDNA Analyzer (Applied Biosystems, Foster City, CA, USA) by using a BigDye Terminator v3.1 Cycle sequencing kit (Applied Biosystems)... Sequences were analyzed by using Sequencher software (Gene Codes Corp., Ann Arbor, MI, USA) and compared with the reference sequence for IHH (NM_002181.3)... In the Chinese family with the p.Glu131Lys variant, the involved brachydactyly sites varied among the different family members as did other hand anomalies such as shortened proximal phalanges of the thumbs and clinodactyly, which suggests the phenotypic variability of BDA1... The Ihh gene, which encodes a member of the Hedgehog family of secreted signaling molecules, is known for its role in mediating condensation, growth, and differentiation of long bone cartilage templates... In an experiment involving Ihh -/- mice, loss of Ihh signaling resulted in a limb reduction phenotype, with a complete lack of osteoblast development in all bones that develop by endochondral ossification, highlighting the role played by Ihh in cartilage differentiation and bone formation... To date, 10 different missense mutations and one deletion have been identified in the Human Gene Mutation Database (HGMD, 2014.3)... Almost all BDA1-causing IHH mutations are missense mutations and are restricted to the N-terminal active fragment spanning codons 95-154. p.Glu131Lys mutation located in the N-terminal fragment affects Hedgehog binding to the receptor Patched1, reducing its capacity to induce cellular differentiation... In conclusion, we identified p.Glu131Lys mutation in the IHH gene.

No MeSH data available.