Categories: Muscle phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 601287 (trait) , 601411 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0011028: autosomal recessive limb-girdle muscular dystrophy type 2F

Mendelian trait/disorder: yes

Mode of inheritance: Probably autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2017

Cross-species summary: Previously known as Muscular dystrophy, limb-girdle, type 2F (LGMD2F): "At the 229th ENMC international workshop, Straub et al. (2018) reviewed, reclassified, and/or renamed forms of LGMD. The proposed naming formula was 'LGMD, inheritance (R or D), order of discovery (number), affected protein.' Under this formula, LGMD2F was renamed LGMDR6." (OMIM 601287)

History: As summarised by Cox et al. (2017), "The first report of LGMD associated with sarcoglycan deficiency in dogs [by Schatzberg and Shelton, 2004] involved three breeds: Chihuahua, Cocker spaniel, and a 7-month-old male Boston terrier from Colorado (case 1), but mutations were not identified. Four years later, sarcoglycanopathy was described again [by Dietz et al., 2008] in an unrelated 4-month-old male Boston terrier from Iowa."

Molecular basis: Cox et al. (2017) reported different likely causal variants in two unrelated Boston Terriers (case 1 above, and an unrelated dog not previously described), the first being a small deletion c.534_535delGA and the second an indel "([Can Fam3.1]chr4:53262018-53262020, ATG > CC), followed by 9 bp that were unchanged before a deletion of 19,403 bp (chr4:53262030-53281432)" Brunetti et al. (2023) sequenced the genome of an affected female 8 month old Lagotto Romagnolo dog "and compared the data to more than 900 control genomes of different dog breeds. Genetic analysis revealed a homozygous private protein-changing variant in the SGCD gene encoding delta-sarcoglycan in the affected dog. The variant was predicted to induce a SGCD:p.(Leu242Pro) change in the protein. In silico tools predicted the change to be deleterious. Other 770 Lagotto Romagnolo dogs were genotyped for the variant and all found to be homozygous wild type."

Clinical features: Cox et al. (2017): "marked muscle weakness and atrophy in the shoulder and hips during puppyhood" Brunetti et al. (2023): "An 8-month-old female Lagotto Romagnolo dog was presented with a 1-month history of an initial severe reluctance to move ... , the dog rapidly ... [progressed] to a marked stiff gait. Dysphagia, dysphonia and polyuria and polydipsia appeared in the last five days prior to the examination. ... The dog showed a progressive rapid worsening of the clinical signs leading in approximately one month to a severe non-ambulatory tetraparesis and severe dysphagia."

Pathology: Brunetti et al. (2023) reported pathologal findings of a single affected Lagotto Romagnolo dog: "Macroscopically, the muscles were moderately atrophic, except for the diaphragm and the neck muscles, which were markedly thickened. Histologically, all the skeletal muscles examined showed atrophy, hypertrophy, necrosis with calcification of the fibers, and mild fibrosis and inflammation. On immunohistochemistry, all three dystrophin domains and sarcoglycan proteins were absent. On Western blot analysis, no band was present for delta sarcoglycan."

Breeds: Boston Terrier (Dog) (VBO_0200204), Lagotto Romagnolo (Dog) (VBO_0200804).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: