ANKH

Gene Facts

• HGNC Symbol: ANKH (HGNC:15492)
• HGNC Name: ANKH inorganic pyrophosphate transport regulator
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: CCAL2, CMDJ
• Alias symbols: HANK, ANK, CPPDD, SLC62A1
• %HI: 40.3
• pLI: 1
• LOEUF: 0.46
• Cytoband: 5p15.2
• Genomic Coordinates:

  GRCh37/hg19:	chr5:14704909-14871887
  GRCh38/hg38:	chr5:14704800-14871778

• MANE Select Transcript: NM_054027.6 ENST00000284268.8
• Function: Transports adenosine triphosphate (ATP) and possibly other nucleoside triphosphates (NTPs) from cytosol to the extracellular space. Mainly regulates their levels locally in peripheral tissues while playing a minor systemic role. Prevents abnormal ectopic mineralization of the joints by regulating the extracellular levels of the calcification inhibitor inorganic pyrophosphate (PPi), which originates from the conversion of extracellular NTPs to NMPs and PPis by ENPP1 (PubMed:32639996, PubMed:35147... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-24929
• ClinGen Curation ID: CCID:006664
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: No Evidence for Haploinsufficiency (0)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 02/23/2022

Haploinsufficiency (HI) Score Details

• HI Score: 0
• HI Evidence Strength: No Evidence for Haploinsufficiency

HI Evidence

• PUBMED: 11326338
  Reichenberger et al (2001) reports three different variants (observed in five different families and in isolated cases) in ANKH in individuals with craniometaphyseal dysplasia (CMD). The variants are two in-frame deletions and one in-frame insertion caused by a splicing defect. All variants cluster within seven amino acids in one of the six possible cytosolic domains of ANKH. The results suggest that the mutated protein has a dominant negative effect on the function of ANKH, since reduced levels of pyrophosphate in bone matrix are known to increase mineralization.
• PUBMED: 22150416
  Dutra et al. (2012) reports two large in-frame deletions in exons 7 and 10 of ANKH from two unrelated patients without the family history of CMD manifesting severe forms of the disorder.
• PUBMED: 20186813
  Zjac et al. (2010) evaluated the ANKH gene in a patient with sporadic CMD and performed in vitro analyses to assess the subcellular targeting of the ANKH protein. They report on an in frame insertion/deletion within exon 7 of ANKH in a male patient clinically diagnosed with a sporadic autosomal dominant form of CMD. Authors also presented in vitro data suggesting that the CMD mutation alters intracellular trafficking of the ANKH protein. Specifically, they performed immunofluorescence microscopy of transduced cells to show that wild-type Ankh protein is localized in both cytoplasmic compartment and plasma membrane (Fig 3B). In contrast, mutant Ankh was distributed only in the intracellular compartment and not on the plasma membrane. The authors postulated that CMD mutation inhibits Ankh protein targeting to the plasma membrane.
• PUBMED: 23390136
  Iqbal et al (2013) report disruption of the ANK3 gene by a balanced translocation in a patient with behavioral problems including ADHD, ASD and cognitive decline. The translocation involved chromosome 2 and 10 detected by metaphase karyotyping. By sequencing analysis, it was determined that on chromosome 2, all isoforms of ANKH were disrupted in its second to last intron. A separate consanguineous family with moderate intellectual disability (ID), an ADHD-like phenotype and behavioral problems was also described in this study in whom a de novo homozygous truncating frameshift mutation in the longest isoform of ANK3 was detected.

• HI Evidence Comments: 1) In-frame deletions and point variants in ANKH cause craniometaphyseal dysplasia (CMD); a bone dysplasia characterized by overgrowth and sclerosis of the craniofacial bones and abnormal modeling of the metaphyses of the tubular bones. Hyperostosis and sclerosis of the skull may lead to cranial nerve compressions resulting in hearing loss and facial palsy. 2) Missense mutations in ANKH cause chondrocalcinosis-2; a common cause of joint pain and arthritis, caused by the deposition of calcium-containing crystals within articular cartilage (Pendleton et al 2002, Williams et al 2003). Also see Kornak et al. (2010; PMID: 20358596) who reports three novel missense mutations in simplex patients with CMD. CMD variants in ANKH typically involve exons 7–10, while variants resulting in chondrocalcinosis (CCAL2) typically involve exons 1, 2, and 12. 3) Although autosomal dominant CMD variants have been reported, it is uncertain if these are true loss of function variants; we have opted not to score any of the in-frame deletions reported. In the Zjac et al 2010 publication above, it is noted that haploinsufficiency alone does not seem to account for the CMD phenotype. It has been reported that haploinsufficiency of Ank in heterozygous mice (Ank +/-) does not cause abnormal skeletal phenotypes, while mice completely lacking Ank expression (homozygous mutants) display skeletal characteristics similar, yet not identical, to autosomal dominant CMD phenotypes in humans [PMID: 17186460). One possible mechanism of CMD is that variants in the ANKH gene result in a loss of ANKH protein expression activity in the plasma membrane, while allowing gain of aberrant function. The latter could be due to mistargeting of ANK to subcellular compartments, as seen in some other mutant proteins (PMID: 20186813). Of note, there has also been an observation of an individual with a intronic homozygous deletion involving this gene and a neurodevelopmental phenotype in addition to skeletal features: Vulto-van Silfhout et al. (2013) described a proband with 81KB intronic (intron 1; chr5:14824247_14905610del81363; hg18 - table S3) homozygous deletion of ANKH by microarray (both parents were carriers of the het form of the del). This was one of the first confirmation of this gene in autosomal-recessive ID, in combination with deafness, joint abnormalities, and hypophosphatemia (PMID: 24038936).

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity