A rare variant in the FHL1 gene associated with X-linked recessive hypoparathyroidism

Hum Genet. 2017 Jul;136(7):835-845. doi: 10.1007/s00439-017-1804-9. Epub 2017 Apr 25.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Exons
  • Female
  • Gene Expression Regulation
  • Genomics
  • HEK293 Cells
  • Humans
  • Hypercalciuria / diagnosis
  • Hypercalciuria / genetics*
  • Hypocalcemia / diagnosis
  • Hypocalcemia / genetics*
  • Hypoparathyroidism / congenital*
  • Hypoparathyroidism / diagnosis
  • Hypoparathyroidism / genetics
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • LIM Domain Proteins / genetics*
  • LIM Domain Proteins / metabolism
  • Male
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Mutation
  • Pedigree
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism


  • FHL1 protein, human
  • Fhl1b protein, zebrafish
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • Muscle Proteins
  • Zebrafish Proteins
  • Calcium

Supplementary concepts

  • Hypercalciuric Hypocalcemia, Familial