Two missense mutations in GPNMB cause autosomal recessive amyloidosis cutis dyschromica in the consanguineous pakistani families.

Abstract

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.

• Authors: Obaid Ur Rahman, Jeena Kim, Caroline Mahon, Musharraf Jelani, Changsoo Kang
• Journal: Genes & genomics (Genes Genomics) Vol. 43 Issue 5 Pg. 471-478 (05 2021) ISSN: 2092-9293 [Electronic] Korea (South)
• PMID: 33687658 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• GPNMB protein, human
• Membrane Glycoproteins

Topics

• Adolescent
• Adult
• Amyloidosis, Familial (genetics, pathology)
• Consanguinity
• Female
• Homozygote
• Humans
• Male
• Membrane Glycoproteins (genetics)
• Mutation, Missense
• Pedigree
• Phenotype
• Skin Diseases, Genetic (genetics, pathology)