A rare variant in the FHL1 gene associated with X-linked recessive hypoparathyroidism
| Autor: | Shay Botchan, Mingyan Fang, Oren Pleniceanu, Benjamin Dekel, Le Cheng, Einat Lahav, Nir Pillar, Noam Shomron, Limor Ziv |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Hypoparathyroidism Hypercalciuria Muscle Proteins Biology medicine.disease_cause 03 medical and health sciences Exon Internal medicine Genetics medicine Animals Humans Zebrafish Genetics (clinical) X-linked recessive inheritance Exome sequencing Original Investigation Regulation of gene expression Mutation Hypocalcemia Intracellular Signaling Peptides and Proteins Exons Genomics LIM Domain Proteins Zebrafish Proteins biology.organism_classification medicine.disease Pedigree 030104 developmental biology Endocrinology HEK293 Cells Gene Expression Regulation Calcium Female Primary Hypoparathyroidism |
| Zdroj: | Human Genetics |
| ISSN: | 1432-1203 |
| Popis: | Isolated familial hypoparathyroidism is an extremely rare disorder, which to date has been linked to several loci including mutations in CASR, GCM2, and PTH, as well as a rare condition defined as X-linked recessive hypoparathyroidism, previously associated with a 1.5 Mb region on Xq26-q27. Here, we report a patient with hypocalcemia-induced seizures leading to the diagnosis of primary hypoparathyroidism. Mutations in CASR, GCM2, and PTH were ruled out, while whole exome sequencing of the family suggested FHL1, located on chromosome Xq26, as the most likely causative gene variant (FHL1, exon 4, c.C283T, p.R95W). Since FHL1 has not been linked to calcium regulation before, we provide evidence for its functional role in hypoparathyroidism by: (i) bioinformatics analysis coupling its action to known modulators of PTH function; (ii) observing strong expression of fhl1b in Corpuscles of Stannius, gland-like aggregates in zebrafish that function in calcium regulation similar to mammalian PTH; and (iii) implicating fhl1b and FHL1 as regulators of calcium homeostasis in zebrafish and human cells, respectively. Altogether, our data suggest that FHL1 is a novel regulator of calcium homeostasis and implicate it as the causative gene for X-linked recessive hypoparathyroidism. Electronic supplementary material The online version of this article (doi:10.1007/s00439-017-1804-9) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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