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KMID : 0381120210430050471
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Genes and Genomics
2021 Volume.43 No. 5 p.471 ~ p.478
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Two missense mutations in GPNMB cause autosomal recessive amyloidosis cutis dyschromica in the consanguineous pakistani families
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Rahman Obaid Ur
Kim Jee-Na
Mahon Caroline
Jelani Musharraf
Kang Chang-Soo
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Abstract
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Background: Amyloidosis cutis dyschromica (ACD) is a rare variant of cutaneous amyloidosis. This disorder often clusters in families, and it has been suggested that genetic factors might be involved in its development.
Objective: To identify the genetic causes of ACD, we recruited a consanguineous Pakistani family with multiple cases of ACD that display a recessive mode of inheritance.
Methods: We performed whole-exome sequencing of samples from 7 members of this family, followed by bioinformatic and in silico analyses to identify the causative variant. For the replication study, we recruited a British family with Pakistani ancestry, and sequenced all exons of glycoprotein non-metastatic melanoma protein b (GPNMB) to identify mutations. We also investigated effects of the mutations on the stability of the GPNMB protein using the I-TASSER three-dimensional modeling tool.
Results: We found a novel homozygous mutation, p.Gly363Val (c.1088 G>T), in GPNMB in all affected cases. In a replication study, another homozygous missense mutation in GPNMB, pIle174Met (c.522 C>G), was carried by the affected son. The two mutations were not observed in our in-house data set comprising 217 healthy Pakistani individuals or in The Genome Aggregation Database. Our structural modeling of GPNMB suggested that p.Gly363Val enhanced its stability, whereas p.Ile174Met caused instability.
Conclusions: This study reports two novel missense mutations in two Pakistani families that cause ACD. The mutations appear to influence GPNMB stability, as revealed by protein modeling.
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KEYWORD
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Amyloidosis cutis dyschromica, Exome sequencing, Autosomal recessive, GPNMB
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