Dwarfism in Tibetan Terrier dogs with an <i>LHX3</i> mutation

Thaiwong, Tuddow; Corner, Sarah; Forge, Stacey La; Kiupel, Matti

doi:10.1177/10406387211007526

Cited by 5 publications

(4 citation statements)

References 19 publications

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“…LHX3 is a marker of early anterior pituitary development [ 22 , 23 , 24 ]. The deletion of this gene leads to an incomplete development of the pituitary gland, resulting in CPHD in both humans and dogs [ 12 , 22 , 23 , 24 , 25 ]. Individuals with CPHD caused by an Lhx3 mutation are deficient in GH and other essential hormones, resulting in short stature [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…In dogs, the Lhx3 gene maps to chromosome 9, and spontaneous mutations in this gene have been identified to cause short stature [ 11 ]. Dwarfism in dogs is due to spontaneous mutations in Lhx3 that are often caused by the shortening of a DNA repeat sequence in intron 5 and is often seen in breeds such as the German Shepherd, Dog Salos, and the Czechoslovakian Wolfdog [ 12 ]. These mutations typically exhibit autosomal recessive inheritance [ 11 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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A Nonsynonymous Substitution of Lhx3 Leads to Changes in Body Size in Dogs and Mice

Dang,

Gao,

Lyu

et al. 2024

Genes

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Lhx3 is a LIM-homeodomain transcription factor that affects body size in mammals by regulating the secretion of pituitary hormones. Akita, Shiba Inu, and Mame Shiba Inu dogs are Japanese native dog breeds that have different body sizes. To determine whether Lhx3 plays a role in the differing body sizes of these three dog breeds, we sequenced the Lhx3 gene in the three breeds, which led to the identification of an SNP in codon 280 (S280N) associated with body size. The allele frequency at this SNP differed significantly between the large Akita and the two kinds of smaller Shiba dogs. To validate the function of this SNP on body size, we introduced this change into the Lhx3 gene of mice. Homozygous mutant mice (S279N+/+) were found to have significantly increased body lengths and weights compared to heterozygous mutant (S279N+/−) and wild-type (S279N−/−) mice several weeks after weaning. These results demonstrate that a nonsynonymous substitution in Lhx3 plays an important role in regulating body size in mammals.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Nonsynonymous Substitution of Lhx3 Leads to Changes in Body Size in Dogs and Mice

Dang,

Gao,

Lyu

et al. 2024

Genes

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“…In contrast, it is challenging to trace the relatives of household dogs after disease onset. In particular, compared with the cases where hereditary diseases or traits are apparent at or shortly after birth [ 22 , 23 , 24 , 25 ], it is more difficult to prove familial transmission of adult-onset genetic diseases, such as hereditary GI polyposis. To overcome this difficulty and demonstrate familial transmission, a previous study examined the blood relationships of five affected JRTs using their pedigree certificates.…”

Section: Introductionmentioning

confidence: 99%

First Evidence of Familial Transmission of Hereditary Gastrointestinal Polyposis Associated with Germline APC Variant in Jack Russell Terriers

Yoneji

Yoshizaki

Hirota

et al. 2023

Veterinary Sciences

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Jack Russell terriers (JRTs) with gastrointestinal (GI) neoplastic polyps have been recently reported to harbor an identical germline variant in the adenomatous polyposis coli (APC) gene, c.[462_463delinsTT], in the heterozygous state, which indicates that this disease is an autosomal dominant hereditary disorder. Many individual cases of this disease have been observed in clinical practice; however, familial transmission has not been demonstrated due to the difficulty in tracing the family members of household dogs, especially after the disease’s onset in adulthood. Recently, we encountered two cases of GI polyposis in maternal half sisters. These two cases facilitated the identification of additional relatives spanning three generations, including parents, full and half siblings of the dam (aunt and uncle), littermate and non-littermate siblings, and a nephew. Genetic analysis revealed that 11 of the 14 examined JRTs in this family carried the heterozygous germline APC variant, and eight dogs with the variant already had a current and/or past medical history of GI neoplastic polyps. Some cases in the family showed significantly more severe disease phenotypes than those initially reported, suggesting that the severity of this disease can vary considerably among individuals. Moreover, familial aggregation of severe cases suggested that the genetic modifier involved in increasing severity may have been transmitted in this family in addition to the germline APC variant. Furthermore, in addition to this family, we reported two other families of JRTs affected by hereditary GI polyposis that consisted of five full and half siblings and a mother–daughter pair, respectively. These findings unequivocally establish the transgenerational transmission of hereditary GI polyposis associated with the germline APC variant in JRT lineages.

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“…Dwarfism may also be caused by congenital hormone deficiency, which typically leads to proportionate dwarfism and a persistent puppy coat. Pituitary dwarfism, caused by an intronic deletion in the LHX3 gene, was described in four genetically diverse dog breeds [ 17 , 18 , 19 ]. Another intronic variant in POU1F1 was found in Karelian Bear dogs with pituitary dwarfism [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

PCYT1A Missense Variant in Vizslas with Disproportionate Dwarfism

Ludwig-Peisker

Ansel²,

Schweizer

et al. 2022

Genes

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Disproportionate dwarfism phenotypes represent a heterogeneous subset of skeletal dysplasias and have been described in many species including humans and dogs. In this study, we investigated Vizsla dogs that were affected by disproportionate dwarfism that we propose to designate as skeletal dysplasia 3 (SD3). The most striking skeletal changes comprised a marked shortening and deformation of the humerus and femur. An extended pedigree with six affected dogs suggested autosomal recessive inheritance. Combined linkage and homozygosity mapping localized a potential genetic defect to a ~4 Mb interval on chromosome 33. We sequenced the genome of an affected dog, and comparison with 926 control genomes revealed a single, private protein-changing variant in the critical interval, PCYT1A:XM_038583131.1:c.673T>C, predicted to cause an exchange of a highly conserved amino acid, XP_038439059.1:p.(Y225H). We observed perfect co-segregation of the genotypes with the phenotype in the studied family. When genotyping additional Vizslas, we encountered a single dog with disproportionate dwarfism that did not carry the mutant PCYT1A allele, which we hypothesize was due to heterogeneity. In the remaining 130 dogs, we observed perfect genotype–phenotype association, and none of the unaffected dogs were homozygous for the mutant PCYT1A allele. PCYT1A loss-of-function variants cause spondylometaphyseal dysplasia with cone–rod dystrophy (SMD-CRD) in humans. The skeletal changes in Vizslas were comparable to human patients. So far, no ocular phenotype has been recognized in dwarf Vizslas. We propose the PCYT1A missense variant as a candidate causative variant for SD3. Our data facilitate genetic testing of Vizslas to prevent the unintentional breeding of further affected puppies.

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Dwarfism in Tibetan Terrier dogs with an LHX3 mutation

Cited by 5 publications

References 19 publications

A Nonsynonymous Substitution of Lhx3 Leads to Changes in Body Size in Dogs and Mice

A Nonsynonymous Substitution of Lhx3 Leads to Changes in Body Size in Dogs and Mice

First Evidence of Familial Transmission of Hereditary Gastrointestinal Polyposis Associated with Germline APC Variant in Jack Russell Terriers

PCYT1A Missense Variant in Vizslas with Disproportionate Dwarfism

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