Categories: Nervous system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 615316 (gene) , 615330 (trait) , 616451 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2023

Species-specific name: Hereditary necrotizing myelopathy

Species-specific symbol: HNM

History: Opmeer et al. (2023): "... the first hereditary disease identified in the [Nederlandse Kooikerhondje] breed was hereditary necrotizing myelopathy [Mandigers et al. 1993]. Cases were seen as of 1962, and eradication of hereditary necrotizing myelopathy by selective breeding only became possible after the discovery of the causative mutation ... [Mandigers et al., 2023] in 2015."

Inheritance: Mandigers et al. (2023): "Pedigree analysis indicated that the disease is inherited as an autosomal recessive trait, probably originating from a single founder (Mandigers et al., 1993)"

Mapping: Mandigers et al. (2023) "investigated the possible cause by a genome-wide analysis using six affected and 17 unrelated unaffected Kooiker dogs. ... The HNM [hereditary necrotizing myelopathy] locus was mapped by a case–control study using a dense SNP array and confirmed by linkage analysis of two pedigrees. ... The basic defect was localized in the centromeric 5 Mb region of canine chromosome 14."

Molecular basis: Mandigers et al. (2023) investigated gene exons in the 5 Mb region on chromosome 14 by next-generation sequencing of affected Kooiker dogs: "A candidate pathogenic mutation was found in the iron–sulfur cluster assembly gene IBA57 and led to the amino acid substitution R147W. ... IBA57 is a nuclear-encoded mitochondrial protein [and defects in the protein are known to cause multiple mitochondrial dysfunction syndrome 3 in humans]. ... The functional effect of the candidate canine IBA57 pathogenic variant was biochemically examined in an established HeLa cell culture model in which the endogenous IBA75 gene product was depleted by RNAi. ... The incomplete functional complementation of IBA57-depleted human cells by IBA57-R147W identifies the DNA mutation in affected Kooiker dogs as the genetic cause of HNM."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Mandigers et al. (2023): "The clinical signs, paresis and ataxia, start in most [affected Kooiker] dogs around the age of 3–12 months in the hind limbs and progresses to tetraparalysis before the age of 2 years."

Pathology: Mandigers et al. (2023): "Post-mortem examination performed in these dogs revealed a symmetric bilateral necrotizing myelopathy with malacia in the ventral and dorsal white matter."

Breed: Nederlandse Kooikerhondje (Dog) (VBO_0200932).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: