OMIA 001887-9913 : Osteopetrosis with gingival hamartomas in Bos taurus

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 166600 , 611490

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2014

History: This disorder was first documented by Sartelet et al. (2014).

Inheritance: Sartelet et al. (2014) reported data consistent with autosomal recessive inheritance.

Mapping: By conducting a GWAS on 33 affected and 275 controls (each genotyped with a custom 50K SNP chip; Charlier et al., 2008, Nat Genet 40, 449-454), Sartelet et al. (2014) mapped this disorder to the proximal end of chromosome BTA25. Subsequent "Visual examination of the SNP genotypes defined a non-recombinant autozygous interval of 1.15 Mb (Bovine Genome assembly bTau6 (UMD3.1), chr25: 632,647-1,781,139) shared by all 33 cases and encompassing 82 annotated transcripts".

Molecular basis: Comparison of whole-genome sequence by Sartelet et al. (2014), from four affecteds and eight control Belgian Blue non-carriers, revealed three SNVs "[c2244G>C + c2248T>C + c2250C>A] located in exon 23 of the CLCN7 gene encoding the anion transport protein ClC-7". The first of these is synonymous, but the second and third jointly cause "a tyrosine to glutamine substitution (TAC>CAA: Y750Q)" in a highly conserved region of the protein. Subsequent genotyping for the two Y750Q missense mutations in "63 cases, 74 of their parents, 141 animals from 11 breeds other than BBCB, and 6,489 healthy BBCB animals" confirmed the causality of these mutations: "All cases were homozygous for the Y750Q mutation, while available parents and putative founder (Gabin) were all carriers. The mutation was absent in the non-BBCB cohort, and detected at a frequency of 5% (644 carriers) in BBCB controls. None of the genotyped controls was homozygous for the mutant (p=0.000026 under Hardy Weinberg equilibrium)."

Clinical features: As reported by Sartelet et al. (2014), "Between 2008 and 2010, we collected biological material with pedigree records for 63 newborn calves with shared symptomatology: affected calves were mostly stillborn (70% of them), slightly premature (gestation length between 210 and 260 days, 73%), displayed a small body size (45%) and abdominal hydrops (58%), an abnormal skull shape (100%), inferior brachygnatism (100%), protruding tongue (81%) and gingival hamartomas of variable size (up to 15 cm diameter, 80%) located on the lower jaw . . . . All calves born alive were blind and consequently euthanized within days or weeks. At necropsy, we observed liver (82% . . . ) and kidney (59% . . . ) hypertrophies. Mothers of affected calves typically suffered from hydramnios, a condition commonly associated with impaired swallowing in the fetus".

Prevalence: Sartelet et al. (2014) reported that 10% of normal Belgian Blues are carriers of the pair of causal mutations.

Breed: Belgian Blue.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
CLCN7 chloride channel, voltage-sensitive 7 Bos taurus 25 NC_037352.1 (1158736..1138163) CLCN7 Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Belgian Blue Osteopetrosis with gingival hamartomas CLCN7 missense c2248T>C + c2250C>A p. Y750Q 2014 24159188

Reference


2014 Sartelet, A., Stauber, T., Coppieters, W., Ludwig, C.F., Fasquelle, C., Druet, T., Zhang, Z., Ahariz, N., Cambisano, N., Jentsch, T.J., Charlier, C. :
A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle. Dis Model Mech 7:119-28, 2014. Pubmed reference: 24159188. DOI: 10.1242/dmm.012500.

Edit History


  • Created by Frank Nicholas on 28 Oct 2013
  • Changed by Frank Nicholas on 28 Oct 2013
  • Changed by Frank Nicholas on 15 Sep 2014
  • Changed by Frank Nicholas on 16 Aug 2016