Genes to Know Flashcards
6 important genes for male sexual differentiation
SRY, SF-1, SOX-9, WT-1, GATA-4, FGF-9
SRY location
Distal p-arm of Y (adjacent to psuedoautosomal region)
SRY function
Activates genes that promote testis development
SRY associated pathology
• XY: Pure gonadal dysgenesis (Swyer syndrome); female phenotype • XX+SRY: XX testicular or ovotesticular DSD (de la Chapelle syndrome)
SRY stands for:
Sex-determining Region Y chromosome
SF-1 stand for:
Steroidogenic factor 1, a nuclear “orphan receptor”
SF-1 gene & location
Encoded by NR5A1 gene (q-arm of chromosome 9)
SF-1 function
Binds and activates the SRY promoter
SF-1 associated pathology
Gain-of-function mutations that cause inappropriate activation of testicular pathways in the XX gonad; described in ~10-20% of XX testicular or ovotesticular DSD cases
SOX-9 location
“gene desert on 17q24”
SOX-9 function
Encodes a transcription factor that functions downstream of SRY and is both necessary and sufficient for testicular development; “SOX-9 is the most likely SRY target gene; virtually all male-female sex reversal can be explained by failure to generate sufficient levels of SOX-9 to promote positive feedback loops”
SOX-9 associated pathology
Deficiency -> skeletal malformation syndrome campomelic dysplasia, cleft palate, and autosomal sex reversal (in XY: pure gonadal dysgenesis, female phenotype)
WT-1 stands for:
Wilms’ tumor protein
WT-1 location
Encoded by the WT1 gene on chromosome 11p
WT-1 function
Transcription factors that can activate promoter of SRY
WT-1 associated pathology
Denys–Drash syndrome (DDS) characterized by gonadal dysgenesis, nephropathy, and Wilms’ tumor vs Frasier syndrome = gonadoblastoma, instead of Wilms’ tumor
GATA-4 location
P-arm of chromosome 8
GATA-4 function
Synergizes with WT-1; transcription factors that can activate promoter of SRY
GATA-4 associated pathology
In mice, mutation leads to a block in testis development and a down-regulation of SRY
FGF-9 stands for:
Fibroblast growth factor
FGF-9 location
Q-arm chromosome 13
FGF-9 function
Once activated by SOX9, it is responsible for forming a feedforward loop with Sox9, increasing the levels of both genes. It forms a positive feedback loop upregulating SOX9, while simultaneously inactivating the female Wnt4 signaling pathway
FGF-9 associated pathology
Mice lacking the homolog gene displayed a male-to-female sex reversal phenotype
3 important genes for female sexual differentiation
DAX-1, WNT-4, RSPO-1
DAX-1 stands for:
Dosage sensitive adrenal hypoplasia
DAX-1 gene & location
Encoded by the NR0B1 gene; p-arm of X chromosome
DAX-1 function
DAX1 -> antagonizes SF1 -> SF1 and SOX9 off -> inhibition of male pathway and WNT 4 activation (expressed only in XX gonads); induces ovarian development
DAX-1 associated pathology
• Duplications (gain-of-function) cause gonadal dysgenesis (inhibiting activity of NR5A1/SF1) • Loss-of-function: • X-linked adrenal hypoplasia/insufficiency (males) • Hypogonadotropic hypogonadism; delayed puberty (females)
WNT-4 stands for:
Wingless family of genes
WNT-4 location
P-arm of chromosome 1
WNT-4 function
Required for female sex development; absence required for male sexual development
WNT-4 associated pathology
• Deficiency: androgen excess, no uterus • Loss-of-function: autosomal recessive SERKAL syndrome (sex reversal with dysgenesis of kidneys, adrenals, and lungs)
RSPO-1 stands for:
R-spondin 1
RSPO-1 location
P-arm of chromosome 1
RSPO-1 function
Interacts with WNT4 in female sexual development
RSPO-1 associated pathology
Loss-of-function -> AR testicular or ovotesticular DSD + palmoplantar hyperkeratosis
5 important genes for folliculogenesis
FOXL-2, BMP-15, GDF-9, C-kit, Neurotrophins
FOXL-2 stands for:
Forkhead box protein L2
FOXL-2 location
Q-arm chromosome 3
FOXL-2 function
Essential for granulosa cell differentiation (GCs never change to a cuboidal shape)
FOXL-2 associated pathology
Causes blepharophimosis/ptosis/epicanthus-inversus syndrome; affects eyelid and causes premature ovarian failure
BMP-15 stands for:
Bone morphogenetic protein 15
BMP-15 location
P-arm of X chromosome
BMP-15 function
• Promotion of growth and maturation of ovarian follicles, starting from the primary follicle • Regulates sensitivity of GCs to FSH (contributes to determining how many eggs are ovulated) • Prevention of GC apoptosis • Promotes developmental competence of oocytes
BMP-15 associated pathology
Mutations have been identified in a small number of women with idiopathic POI
GDF-9 stands for:
Growth/differentiation factor 0
GDF-9 location
Q-arm of chromosome 5
GDF-9 function
Signals via serine-threonine kinase receptors, produced by oocytes in primary and larger follicles to stimulate glycolysis, amino acid transport, and cholesterol synthesis in granulosa cells
(absent in primordial follicles)
GDF-9 associated pathology
Mutation in mice prevents follicle development beyond primary stage and absence of thecal markers, and eventual oocyte death
C-kit stands for:
Kit-ligand
C-kit location
Q-arm chromosome 12
C-kit function
Expressed on GCs of growing follicles; primordial germ cells survival during migration to gonads
C-kit associated pathology
Mutations lead to failure of follicular growth beyond primary stage
Neurotrophins involved in folliculogenesis (5)
NGF, BDNF, NT-3, neurotrophin 4/5
Neurotrophin function
Exert their actions via binding to high affinity trans membrane tyrosine kinase receptors. Promote early proliferation of ovarian mesenchymal cells during early follicular assembly.
What does SHOX stand for?
Short stature homeobox-containing gene
Where is SHOX located?
Pseudoautosomal region (PAR1) of the X chromosome (Xp22.33) and Y chromosome
What does SHOX gene do?
Homeobox gene - helps to regulate development
What does a mutation in SHOX gene cause?
Haploinsufficiency (due to single X chromosome) = cause of short stature in women with Turner’s
Extra copies of SHOX may be a cause of the increased stature seen in other sex chromosome aneuploidy conditions such as triple X, XYY, Klinefelter
Where is KAL-1 located?
p-arm of X chromosome; encodes Anosmin 1 protein
What is the function of KAL-1?
Part of fibronectin family, responsible for cell adhesion and protease inhibition
What is the associated pathology of KAL-1?
X-linked Kallman’s syndrome (failure of olfactory and GnRH neuronal migration)
Where is FGFR1 (KAL-2) located?
p-arm of chromosome 8
What is the funciton of FGFR1 (KAL-2)?
Essential for development and organization of mesoderm-derived tissues and MSK system
What is the pathology associated with FGFR1 (KAL-2)?
Associated Pathology: Autosomal dominant Kallman’s syndrome (~10% of Kallman’s cases)
Where is PROK2 (KAL-4)/prokineticin-2 located?
p-arm of chromosome 3
What is the function of PROK2 (KAL-4) (prokineticin-2)?
Important for neurogenesis
What is the pathology associated with PROK2 (KAL-4) (prokineticin-2)?
Autosomal recessive Kallman’s syndrome; can be normosmic or anosmic
Where is FMR-1 (fragile X mental retardation 1) located?
q-arm of X chromosome (terminal end)
What is the function of FMR-1 (fragile X mental retardation 1)?
Essential for normal cognitive development and female reproductive function
What is the associated pathology with FMR-1 (fragile X mental retardation 1)?
Associated Pathology: >200 CGG repeats -> POI vs Fragile-X associated tremor/ataxia (men after 50)
Where is AZF located?
q-arm of Y chromosome
What is the function of AZF?
Involved in spermatogenesis
What pathology is associated with AZF?
Deletions in the AZF (azospermia factor) A (“awful”) or B (“bad”) typically result in azoospermia
Deletions in AZF C region cause infertility of varying severity, ranging from oligospermia to azoospermia
25% have small testicular volume
Where is KISS1R (kisspeptin) located?
q-arm of chromosome 1
What is the pathology associated with KISS1R (kisspeptin)?
Associated Pathology: Gain-of-function mutation in KISS1 (or receptor KISS1-R) -> precocious puberty; loss-of-function mutation -> hypo-hypo
What is the function of KISS1R (kisspeptin)?
Initiating secretion of GnRH at puberty
Where is PIT-1 (Pituitary-specific positive transcription factor 1) located?
p-arm chromosome 3
Where is GNAS (Guanine Nucleotide binding protein, Alpha Stimulating activity polypeptide) located?
q-arm chromosome 20
What is the function of GNAS (Guanine Nucleotide binding protein, Alpha Stimulating activity polypeptide)?
Somatic mutation of the alpha subunit of the Gs protein (GNAS) activates adenylyl cyclase -> constitutively active adenylate cyclase converting ATP to cAMP -> activation of protein kinase A
What is the associated pathology with GNAS (Guanine Nucleotide binding protein, Alpha Stimulating activity polypeptide)?
Associated Pathology: McCune-Albright Syndrome - triad of peripheral precocious puberty, irregular café-au-lait (“coast of Maine”) skin pigmentation, and fibrous dysplasia of bone
What is the function of PIT-1 (Pituitary-specific positive transcription factor 1)?
Transcription factor necessary for growth and differentiation of anterior pituitary cells; necessary for regulation of genes encoding PRL, GH, and TSH
What is the pathology associated with PIT-1 (Pituitary-specific positive transcription factor 1)?
Associated Pathology: see PROP-1
From PROP-1: “Inactivating mutation -> deficiencies in LH, FSH, GH, PRL and TSH; most likely cause of hypogonadotropic hypogonadism”
Where is PROP-1 (Homeobox protein prophet of PIT-1) located?
q-arm of chromosome 5
What is the function of PROP-1 (Homeobox protein prophet of PIT-1)?
Transcription factor that regulates expression of PIT-1
What is the pathology associated with PROP-1 (Homeobox protein prophet of PIT-1)?
Associated Pathology: Inactivating mutation -> deficiencies in LH, FSH, GH, PRL and TSH; most likely cause of hypogonadotropic hypogonadism
